Drugs of abuse and addiction: A slippery slope toward liver injury

Accepted Manuscript Drugs of abuse and addiction: a slippery slope toward liver injury Dr. Dijendra Nath Roy, PhD, Assistant Professor, Ritobrata Goswami PII:

S0009-2797(15)30071-5

DOI:

10.1016/j.cbi.2015.09.018

Reference:

CBI 7475

To appear in:

Chemico-Biological Interactions

Received Date: 1 June 2015 Revised Date:

14 September 2015

Accepted Date: 18 September 2015

Please cite this article as: D.N. Roy, R. Goswami, Drugs of abuse and addiction: a slippery slope toward liver injury, Chemico-Biological Interactions (2015), doi: 10.1016/j.cbi.2015.09.018. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Review Article (Special Issue for DILI)

Drugs of abuse and addiction: a slippery slope toward liver injury DijendraNath Roy1*, Ritobrata Goswami2 1

Department of Bio Engineering, National Institute of Technology (NIT)-Agartala, West Tripura, Tripura - 799046, India

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Institute of Life Sciences, Ahmedabad University, Ahmedabad - 380009, Gujarat, India

*Corresponding Author

Dr. Dijendra Nath Roy, PhD Assistant Professor Department of Bio Engineering National Institute of Technology (NIT) Agartala Barjala, Jirania, West Tripura, Tripura - 799046, India Mobile: +91-8974264812 Email id: [email protected] 1

ACCEPTED MANUSCRIPT Abstract

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Substances of abuse induce alteration in neurobehavioral symptoms, which can lead to simultaneous exacerbation of liver injury. The biochemical changes of liver are significantly observed in the abused group of people using illicit drugs or drugs that are abused. A huge amount of work has been carried out by scientists for validation experiments using animal models to assess hepatotoxicity in cases of drugs of abuse. The risk of hepatotoxicity from these psychostimulants has been determined by different research groups. Hepatotoxicity of these drugs has been recently highlighted and isolated case reports always have been documented in relation to misuse of the drugs. These drugs induce liver toxicity on acute or chronic dose dependent process, which ultimately lead to liver damage, acute fatty infiltration, cholestatic jaundice, liver granulomas, hepatitis, liver cirrhosis etc. Considering the importance of drug-induced hepatotoxicity as a major cause of liver damage, this review emphasizes on various drugs of abuse and addiction which induce hepatotoxicity along with their mechanism of liver damage in clinical aspect as well as in vitro and in vivo approach. However, the mechanisms of drug-induced hepatotoxicty is dependent on reactive metabolite formation via metabolism, modification of covalent bonding between cellular components with drug and its metabolites, reactive oxygen species generation inside and outside of hepatocytes, activation of signal transduction pathways that alter cell death or survival mechanism, and cellular mitochondrial damage, which leads to alteration in ATP generation have been notified here. Moreover, how the cytokines are modulated by these drugs has been mentioned here.

Keywords: Illicit drugs, Psychoactive drugs, Hepatotoxicty, Liver Function and Injury, Mitochondria, Cytokines modulation

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ACCEPTED MANUSCRIPT Contents: 1. Introduction 2. Clinical and pathological symptomsand risk factors 3. Mechanisms of hepatotoxicity 3.1. Cocaine 3.1.1. Research findings

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3.1.1.1. In vitro studies 3.1.1.2. In vivo studies 3.1.1.3. Clinical studies 3.2. Amphetamine

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3.2.1. Research findings 3.2.1.1. In vitro studies

3.2.1.3. Clinical studies 3.3. Oxycodone 3.3.1. Research findings 3.3.1.1. In vitro studies 3.3.1.2. In vivo studies 3.3.1.3. Clinical studies

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3.4. Heroin

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3.2.1.2. In vivo studies

3.4.1. Research findings

3.4.1.1. In vitro studies 3.4.1.2. In vivo studies

3.5. Nicotine

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3.4.1.3. Clinical studies

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3.5.1. Research findings

3.5.1.1. In vitro studies

3.5.1.2. In vivo studies 3.5.1.3. Clinical studies

3.6. Methadone

3.6.1. Research findings 3.6.1.1. In vitro studies 3.6.1.2. In vivo studies 3.6.1.3. Clinical studies 3.7. Cannabis/Marijuana 3

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3.8.1.1. In vitro studies 3.8.1.2. In vivo studies 3.8.1.3. Clinical studies 3.9. Meperidine

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3.9.1. Research findings 3.9.1.1. In vitro studies

3.9.1.3. Clinical studies 3.10. Hydromorphone 3.10.1. Research findings 3.10.1.1. In vitro studies 3.10.1.2. In vivo studies 3.10.1.3. Clinical studies

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3.11. Chemotherapeutic drugs

3.11.1. Clinical Research findings

5. Conclusion

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6.References

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4. Cytokine modulation in drug-induced liver injury

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1. Introduction: This review is aimed to discuss the toxic effect of drugs of abuse and addiction in liver by providing a global overview and analysis of developments of hepatotoxicity, based on the best available data in ‘pubmed’. This article also provides the global information of latest advancement in hepatotoxicity developed in users of illicit drugs including cannabis, cocaine, amphetamine, opioids, methadone, nicotine, oxycodone etc. termed as substancesof addiction. The article considers the research findings published by different groups using in vivo,in vitro models and human studies understanding the effect of exposure to substance of abuse within laboratory scope. Usage of Illicit drugs can have a profoundly negative effect on a person’s health. It can lead to premature death as evident in cases of overdose, but can also severely curtail the quality of life through disability (any short-term or long-term health loss), such as liver disease, or infection with HIV and hepatitis B and C as a result of sharing contaminated needles or syringes [1]. A study published in 2010reveal that drug dependence on illicit drugs was responsible for a staggering 3.6 million years of life lost through premature death and 16.4 million years of life lived with disability globally. The increase in the global burden of disease from cannabis, amphetamine and cocaine dependence between 1990 and 2010 is essentially attributable to population growth; but this is not the case for opioid dependence, which contributed most to the burden of disease. It has been observed that the demand for illicit drugs varied depending upon the geographic region with cannabis use being more prevalent in Africa, North America, and Latin America while opioids are preferred in Asia and Europe and cocaine in Latin America and in the Caribbean islands. The adverse health is a major issue of those people using the illicit substances for the purpose of addiction [2, 3]. The impact of drug abuse and dependence can affect almost every organ in the human body. The illicit drugs usually weaken the immune system, increasing susceptibility to infections. It can cause abnormal cardiovascular conditions ranging from abnormal heart rate to heart attacks. Injected illicit drugs without doctors’ advice can also lead to collapsed heart valves and infections of the blood vessels of abusers. Moreover, the use of these substances causes the liver to have to work harder, possibly causing significant damage or liver failure as liver is responsible for detoxification. A report stated that nearly 4% of pregnant women in the United States use illicit drugs such as marijuana, cocaine, ecstasy, derivatives of amphetamine, and heroin. These illicit drugs may pose various risks for pregnant women and their unborn babies. Some of these drugs can cause a baby to be born too small or premature, or to have withdrawal symptoms, birth defects or learning and behavioural problems [4]. Hepatotoxicity usually arises hours to a few days after an acute overdose, generally following or accompanying with involvement of other major organs. The clinical phenotype of illicit drugs induced hepatotoxicity is usually acute hepatic necrosis. Initially, serum aminotransferase and LDH levels are markedly elevated with increase in alkaline phosphatase. Liver histology usually shows necrosis and fatty change that resemble ischemic hepatitis or liver injury due to hyperthermia and some related factors that may partially mediate the hepatotoxic effects of illicit drugs. In this article, we will be highlighting the mechanisms involved in liver injury induced by eleven important drugs of abuse and addiction including Cocaine, Amphetamine, Oxycodone, Heroin, Nicotine, Methadone, Cannabis/Marijuana, Fentanyl, Meperidine, Hydromorphone and chemotherapeutic drugs.

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Clinical Symptoms

Cocaine

The main risk factors for cocaine abuse are concomitant use of other illicit drugs, cigarette smoking, alcohol consumption, unemployment, poor education and psychiatric disorders such as anxiety anddepression [5, 6].

Amphetamine

The amphetamine abusers have mainly psychiatric disorder and mood disorder. This patient group poses a high risk for exposure to Hepatitis C virus (HCV). A recent study from China reported that 43% Amphetamine users were exposed to HCV [10, 11]. Being male, having another existing psychological problem, Suffering from anxiety, depression, or loneliness.

Cocaine abuse can elevate the liver enzymes from mild to severe level. Nonparenteral cocaine users can have mild elevation of transaminases and alkaline phosphatase. Physical and mental deterioration, depresseion, agitation, nervousness, tired but unable to sleep, loss of the smell sense, nosebleeds, difficulty in swallowing, chronically runny nose [7, 8]. Irregular sleeping schedule, a lack of awareness of pain, anxiety, depression, confusion, poor performance in memory or cognitive ability, bipolar disorder, personality disorders, schizophrenia, various phobias and paranoia etc. Dizziness, itching track marks on arms and legs, headaches, dry mouth, constipation, nausea and vomiting, lightheadedness; Hallucinations, Paranoia; Mood swings, depression, euphoria,

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Oxycodone

Pathophysiological manifestation due to liver injury Acute hepatocellular injury, acute rhabdomyolysis, coagulative-type perivenular and midzonal necrosis, periportalmicrovesicular fatty change [9].

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Risk Factors

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Drugs

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2. Clinical and pathological symptoms One of the most challenging disorders encountered by gastroenterologists is drug-induced liver injury (DILI). There are two main forms of DILI: intrinsic and idiosyncratic. The former refers to liver toxicity affecting all individuals albeit with different degree while the later hepatotoxicity affects rare individuals. In addition, chronic DILI refers to the inability of liver enzymes to return back to the baseline level. The risk factors along with clinical symptoms are very much critical for a clinician to evaluate of liver damage mediated by drug of abuse and addiction. The major risk factors, clinical symptoms, pathophysiological appearance of the liver injury caused by the following drugs are given below in table 1.

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Liver inflammation, elevation of serum bilirubin and prothrombin time, decrease of serum albumin levels, acute hepatic necrosis [12].

Oxycodone is not been convincingly linked to instances of clinically acute liver injury. However, oxycodone with other opioidacetaminophen combinations has become a common cause of acute

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Home and peer influence, teen age, depression, schizophrenia, posttraumatic stress disorder, other substance (e.g. alcohol) users.

Methadone

Ageing, sleep apnea, polysubstance users for addiction, Medically compromised [16].

Cannabis /Marijuana

A population based study in the United States found high occurrence of cannabis use in patients with schizophrenia, mania, panic disorder and major depression. There is a strong relationship between cannabis abuse and abuse of alcohol, opiates, stimulants and sedatives [18, 19]. A history of abusing nonopiate drugs, A physical condition that causes chronic pain, A cooccurring mental health

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Degenerative vesicular observed, changes in fat, chronic hepatitis, cirrhosis, sedimentation of pathologic protein amyloidosis, dysplastic changes [14].

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Nicotine

liver injury Cholestatic hepatitis [13].

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Being male, peer pressure, other psychological or mental illness, lack of family involvement, conduct disorder in childhood.

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Heroin

anxiety, irritability, becoming socially withdrawn. Depression, bipolar disorder, panic and anxiety disorders, eating disorders (anorexia, bulimia, binge eating disorder, orthorexia, body dysmorphic disorder), post-traumatic stress disorder, obsessive compulsive disorder, personality disorders, schizophrenia, various phobias and compulsions. Decreases the appetite, boosts mood, creates more saliva and phlegm, increases heart rate by around 10 to 20 beats per minute, increases blood pressure by 5 to 10 mmHg, sweating, nausea, and diarrhoea. Drowsiness, weakness, nausea, vomiting, constipation, headache, dry mouth, itchiness, lack of appetite, sweat, flush and weight gain. Cannabis cannot induce acute hepatotoxicity individually. It can be a serious liver toxicant with alcohol consumption, even in Hepatitis C infected person [20].

Swelling in hands and feet, constipation, nausea, vomiting, feeling weak, tired, weak breathing, rapid heart rate, difficulty 7

Fibrotic changes in liver [15].

Pathophysiological manifestation of liver damage is not observed like other illicit drug for either chronic or acute use [17]. Cannabis is responsible in progression of liver fibrosis, steatosis with other factors those are usually liver intoxicant [20].

Clinical manifestation of liver injury with only Fentanyl is not observed till date [21].

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Diarrhoea, loss of appetite, nausea/vomiting, fatigue, hair loss, fever, easy bruising, sores around the mouth, flu-like body pain, constipation, late-developing side effects.

This group of drugs do not have a unique clinical or histological signature that is distinct from other DILI causing agents [22].

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Enhancement of liver marker enzymes [15].

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Chemotherapeutic drugs

Sleep apnea, sleep disorders, pulmonary disorders, morbid obesity, postoperative status (particularly after upper abdominal or thoracic surgery). This group of drugs is used for treating cancer patients [22].

Compulsive physical cravings for Meperidine, negative symptoms experienced when not using Meperidine, requesting Meperidine as a specific treatment option, feigning an injury in order to be taken to emergency room hoping for a Meperidine fix. Dizziness, nausea, vomiting, sedation and sweating.

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Hydromorphone

in concentrating, confusion, dizziness, drowsiness, unconsciousness, coma.

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disorder, especially depression, A chronic condition that requires a long-term prescription for opioids. Psychological causes, such as abuse or underlying trauma, could influence an individual to become addicted to a painkiller such as Meperidine.

Impaired hepatic function involving increased liver enzyme activity.

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Table 1: Summary of risk factors, clinical symptoms and pathological manifestation of abused drugs responsible for liver injury.

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3. Mechanisms of hepatotoxicity

The research findings of each of the following drugs have been segregated into in vitro, in vivo and human or patient studies. However, chemotherapeutic drugs have been segregated based on the types of drugs used. 3.1. Cocaine

Cocaine is a strong central nervous system stimulant that increases levels of the neurotransmitter dopamine in brain circuits regulating pleasure and movement. Normally, dopamine is released by neurons in these circuits in response to potential rewards (like the smell of good food) and then recycled back into the cell that released it, thereby shutting off the signal between neurons. Cocaine prevents the dopamine from being recycled, causing excessive amounts to build up in the synapse or junction between neurons. This amplifies the dopamine signal and ultimately disrupts normal brain communication. It is this flood of dopamine that causes cocaine’s characteristic ‘high’. Some users 8

ACCEPTED MANUSCRIPT will increase their dose in an attempt to intensify and prolong their high level of pleasure, but this can also increase the risk of adverse psychological or physiological effects. Cocaine affects the body in a variety of ways. It constricts blood vessels, dilates pupils, and increases body temperature, heart rate, and blood pressure. It can also cause headaches and gastrointestinal complications such as abdominal pain and nausea. Because cocaine tends to decrease appetite, chronic users can become malnourished as well. Besides its toxicity for the cardiovascular system, central nervous systems, cocaine causes liver injury in human and animal models [23, 24].

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3.1.1. Research findings 3.1.1.1. In vitro studies

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Most of the studies performed to understand the hepatic toxicity of cocaine involve in vivo experiments. Nonetheless there are some studies which used in vitro experiments. In 1990, a group of scientists reported that cocaine and lidocaine interfere with epinephrine-induced changes in intracellular calcium concentration and glucose efflux from rat hepatocytes. Their results highlighted that cocaine and lidocaine decrease the ability of epinephrine to stimulate glucose efflux by interfering with the calcium-mediated, and not the cAMP-mediated intracellular pathway. It is therefore speculated that alterations in metabolic endocrine regulation may contribute to cocaine induced hepatotoxicity [25]. To check cocaine-induced changes in perfusion pressure and bile flow in perfused rat livers, perfusion pressure was measured in a constant flow system. A 15-min infusion of cocaine (1.47 mM) increased perfusion pressure (136+15%), decreased bile flow (61+5%), and decreased oxygen uptake (82+5%). These acute effects of cocaine in the perfused liver were vascular (vasoconstriction) and functional (alteration in bile formation)[26]. Morphological and biochemical changes in mitochondriawas reported early in the course of cocaine-induced hepatotoxicity. This study was designed to evaluate the functional abnormalities of hepatic mitochondria accompanied with lipid peroxidation caused by cocaine, supporting the hypothesis that mitochondria is one of the major intracellular targets of cocaine hepatotoxicity [27]. Short term-cultured rat hepatocytes exposed to cocaine showed that cytochrome P450 modulated the rate of oxidative biotransformation of cocaine to norcocaine and to other metabolites in vitro. Glutathione depletion with buthioninesulfoximine both increased the covalent binding of cocaine to hepatic macromolecules and augmented the inhibitory effect on protein biosynthesis. The results indicate that in rat hepatocytes a high proportion of intracellular cocaine is converted to a reactive metabolite which irreversibly binds to protein, and irreversible binding of cocaine to hepatic protein is associated with impairment of hepatocellular function that could play a role in cocaine-mediated hepatotoxicity [28]. Cocaine is first N-demethylated to norcocaine, followed by oxidation to Nhydroxynorcocaineand norcocainenitroxide radicals. On the basis of ESR studies, the reaction is reported to be accompanied by formation of superoxide and lipid peroxyl radicals [29]. Cocaine hydrochloride was added to primary cultures of hepatocytes isolated from Sprague-Dawley rats to show the in vitro effect of the drug [26]. Cocaine showed its cytotoxicity as measured by lactate dehydrogenase release, to cells from 1mM or it is greater concentration [26]. 3.1.1.2. In vivo studies Cocaine-induced hepatotoxicity in mice was first reported in 1978, which paved the way to understand how cocaine-induced toxicity studies were important to the society [30]. That ethanol administration enhances cocaine-induced hepatotoxicity was reported in 1981 [31]. Involvement of 9

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FAD-containing monooxygenase was found in cocaine-induced hepatotoxicity [32]. Norcocainenitroxide, a potential toxic metabolite of cocaine for liver was found to be produced via the one-electron oxidation of N-hydroxynorcocaine by hepatic microsomal enzymes in cocaineinduced rats in the presence of an NADPH-generating system [33].The hepatotoxicity of cocaine in the mouse was linked with a significant amount (greater than 2 nmol/mg) of irreversible binding of a cocaine metabolite to hepatic protein [34]. The first ultrastructural change was observed through dilatation of rough endoplasmic reticulum in centrilobular hepatocytes following cocaine injection, along with onset of increased conjugated diene absorption in microsomal lipids [35]. Serum glutamic-pyruvic transaminase (SGPT) activities were determined 24 hours after intraperitoneal (i.p) administration of cocaine (20 to 100 mg/kg), by which it has been established that sex and strain differencesmake different hepatotoxic response to acute cocaine administration in the mouse[36]. The depletions of hepatic GSH, NADH, NADPH and ATP coupled with significant increases in oxidized glutathione were observed in mouse [37]. Cocaine is reported to produce either periportal or midzonal necrosis in mice pre-treated with the enzyme inducer phenobarbitone. Significant elevations of plasma AST and ALT were observed 3 hours after cocaine administration and sustained for 12 hours, by which progressive hepatocyte damage had developed into a network of confluent necrosis at the periphery of the periportal region [38].The effects of daily cocaine administration for up to 14 days were studied to understand hepatic morphology and the expression of cytochrome P450 (CYP) enzymes in the mouse liver. Daily intraperitoneal doses of 60 mg/kg of cocaine for 3 days induced severe hepatocellular necrosis in the pericentral zone and decreased activities of CYP1A2, CYP2A4/5, and CYP2Cx[39]. Membrane potential of hepatic mitochondria after acute cocaine administration in rats showed a non-specific calcium dependent inner membrane permeability transition (pore opening) accounted for the partial loss of mitochondrial coupled functions at a period of cocaine intoxication when no cell damage occurred. The level of mitochondrial glutathione played a critical role in protecting inner membrane functional integrity against cocaine-induced oxidative stress[40].Localization of induced accumulation of heat shock proteins including hsp25 and hsp70i was found to shift within the lobule in parallel with the necrotic lesion in mice. These observations indicate a strong spatial correlation within the lobule between cocaine reactive metabolite formation, induced accumulation of hsp25 and hsp70i, and cytotoxicity (necrosis)[41].Cocaineinduced liver injury in mice mediated by nitric oxide and reactive oxygen species revealed that a hydroxyl radical produced by the reaction of nitric oxide and superoxide anion via peroxynitrite may be involved in the pathogenesis of cocaine hepatotoxicity [42]. The progression of sub-acute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanied by the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity [24]. 3.1.1.3. Clinical studies There are couple of studies which investigated the effect of cocaine-induced liver injury in patients. A case report published in 1987 reported that post-mortem examination of liver showed marked periportal inflammation and necrosis, and mild diffuse fatty infiltration of a patient, who died due to cocaine-induced hepatonecrosis [43]. In 1990, another case report highlighted that one patient had 10

ACCEPTED MANUSCRIPT zone-1 necrosis and two others showed well-demarcated zone-3 necrosis in liver. All the patients had mild large- and small-droplet steatosis in surviving hepatocytes. Patients typically have early marked increase and rapid decrease of serum aminotransferases, mild-to-moderate increase in prothrombin time, myoglobinuria, and moderate azotemia. The predominant pattern of zone-3 necrosis is similar to that reported of mice given cocaine [44]. 3.2. Amphetamine

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Amphetamine and derivatives of amphetamines, including methamphetamine, methylphenidate (Ritalin), and methylenedioxymethamphetamine(ecstasy) etc. predominantly releaseneurotransmitters, principally catecholamines by two apparent primary mechanisms. The first one includes the redistribution of catecholamines from synaptic vesicles to the cytosol and induction ofreverse transport of transmitter through plasma membrane uptake carriers while the second one depends on additional drug effects that affect extracellularcatecholamine levels, including uptake inhibition, effects on exocytosis, neurotransmitter synthesis, and metabolism.Clinical evidence has shown that the liver is a target organ of amphetamine and derivatives of amphetamines toxicity. The exact cellular and molecular mechanisms involved in hepatotoxicity by these drugs are under investigation. A few research reports including case study are available in the literature. 3.2.1. Research finding 3.2.1.1. In vitro studies

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Methamphetamine is a powerful central nervous system stimulating drug that also possesses significant adrenergic activity. The cellular pathways involved in methamphetamine liver toxicity were investigated in freshly isolated rat hepatocytes. Methamphetamine cytotoxicity was associated with reactive oxygen species (ROS) formation, lipid peroxidation and rapid glutathione (GSH) depletion which is the third marker of cellular oxidative stress. The results showed that the hepatocyte mitochondrial membrane potential (ΔΨm) was rapidly diminished by methamphetamine;whilesubsequent changes in mitochondrial membrane conformation and cytochrome c release into the cytosol causedcollapsed mitochondrial system [45]. Another study revealed a time- and temperature-dependent mortality of HepG2 cells exposed to 3,4methylenedioxymethamphetamine, methamphetamine, 4-methylthioamphetamine and Damphetamine, individually or in combination. At 37°C, 24-h exposure caused HepG2 cell death preferentially by apoptosis, while a rise to 40.5°C favoured necrosis. ATP levels remained unaltered when the drugs where tested at normothermia, but incubation at 40.5°C provoked marked ATP depletion for all treatments. Further investigations on the apoptotic mechanisms triggered by the drugs (alone or combined) showed a decline in BCL-2 and BCL- XL mRNA levels with concurrent upregulation of BAX, BIM, PUMA and BID genes. Elevation of Bax, cleaved Bid, Puma, Bak and Bim protein levels were also observed. To the best of our knowledge, Puma, Bim and Bak have never been linked with the toxicity induced by amphetamines. Time-dependent caspase-3/-7 activation, but not mitochondrial membrane potential (∆ψm) disruption, also mediated amphetamine-induced apoptosis. Overall, for all evaluated parameters no relevant differences were detected between individual amphetamines and the combination (all tested at equi-effective cytotoxic concentrations), suggesting that the mode of action of the amphetamines in combination does not deviate from the mode of action of the drugs individually when eliciting HepG2 cell death [46]. In another set of 11

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experiments, freshly isolated rat hepatocytes were incubated for 2-h with concentrations of damphetamine used in vivo.A single treatment with d-amphetamine induced glutathione depletion with no effect on lipid peroxidation or cell viability. Furthermore, d-amphetamine potentiated the induction of cell death process of hepatocytes at higher concentration. It is concluded that the aforementioned modifications induced by d-amphetamine (in vivoconcentration) are cytotoxic to freshly isolated rat hepatocytes [47].Hepatocellular damage has been reported as a consequence of 3,4-methylenedioxymethamphetamine intake. This study was undertaken to evaluate the effects of 3,4-methylenedioxymethamphetamine on cell viability as well as free calcium levels [Ca2+] in shortterm cultured hepatocytes. A sustained rise of [Ca2+] after incubation with MDMA induced GSH deficits is observed that correlates with the propensity to increase lipid peroxidation [48]. Exposure to MDMA caused apoptosis of freshly isolated rat hepatocytes and of a cell line of hepatic stellate cells (HSC), as shown by chromatin condensation of the nuclei and accumulation of oligonucleosomal fragments in the cytoplasm. In both cell types apoptosis correlated with decreased levels of bcl-x(L), release of cytochrome c from the mitochondria and activation of caspase 3. In HSC, but not in hepatocytes, MDMA induced poly (ADP-ribose) polymerase (PARP) proteolysis. These results suggest that apoptosis of liver cells could be involved in the hepatotoxicity of MDMA [49].

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Few studies have been designed in vivo to test the toxicity of amphetamine-induced liver injury. Cotreatment of mice with methamphetamine and amphetamine resulted in a significant increase in the hepatocellular necrosis produced by CCl4 as indicated by changes in serum alanine aminotransferase activity and by histopathological examination. The ability of methamphetamine to potentiate CCl4 hepatotoxicity was dose-related and became statistically significant at methamphetamine doses of 10 mg/kg or greater [50, 51]. MDMA-induced TNF-α initiates apoptosis in hepatocytes by triggering multiple mechanisms that include activation of pro-apoptotic (BID, SMAC/DIABLO) and inhibition of anti-apoptotic (NF-κB, Bcl-2) proteins [52]. Amphetamine has been shown previously to increase levels of the inducible 70-kDa heat shock protein (hsp70i) in mouse liver [53]. One group showed for the first time that MDMA causes the oxidative inactivation of key mitochondrial enzymes, which most likely contributes to mitochondrial dysfunction and subsequent liver damage in MDMAexposed animals [54]. 3.2.1.3. Clinical studies

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Prenatal exposure to methamphetamine has been linked to intrauterine growth retardation and variety of withdrawal symptoms. Neonatal cholestasis is rare but a serious problem that indicate hepatobiliary dysfunction and has several categories of aetiologies. This finding was observed and recorded in case of neonatal cholestasis related to prenatal exposure to methamphetamine [55]. A female aged 18 years who had regularly taken 1-2 tablets of methylenedioxymethamphetamine ('ecstasy') every weekend developed acute liver failure [56]. 3,4-Methylenedioxymetamphetamine ("ecstasy") has previously been reported to accelerate hepatic fibrosis [57]. The clinical history of 62 patients with acute liver failure admitted due to ecstasy-induced severe hepatitis had been studied. Ecstasy is responsible for a relatively high number of cases of acute liver failure in young people[58]. 3.3. Oxycodone Oxycodone is one of the many opioid alkaloids found in poppy seeds that acts as analgesic to provide relief from pain. It is used as an alternative to morphine. The formulation of oxycodone is 12

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known as oxycontin and is a highly addictive drug. The drug is classified as a step 2 drug by WHO when used with NSAID agent. Plasma half-life of oxycodone is about half of morphine and is independent of the route of administration [59]. It binds to the μ, δ, and κ receptors, which are coupled to the G-proteins while its affinity with the receptors is a fraction when compared with morphine [60]. Oxycodone leads to a reduction of cAMP and an increase in K+ ion flow. The adenylyl cyclase is also inhibited [60]. Oxycodone is used to alleviate from pain affecting different body parts including somatic pain, visceral pain and neuropathic pain and also from cancer pain [60, 61]. Oxycodone usage leads to various side effects including sedation and nausea [62]. It is found oxycodone does not induce liver injury, rather when it is tableted with acetaminophen (paracetamol) causes of liver injury. Interestingly, oxycodone with ibuprofen in tablated form does not induce liver injury. Overdose of oxycodone could turn fatal if not treated properly. Tolerance to the drug could result after prolonged use and that would lead the user to increase the dose of the drug without approval. According to Centers for Disease Control and Prevention (CDC, USA), the number of poisoning deaths is on the rise and the deaths have been highest among the 45-54 age group. Most of these deaths involve prescription opioid painkillers.

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The clinical studies have been reported only till date on the toxicity of the oxycodone. Toxicity from oxycodone poisoning includes pupil dilation, reduced respiration and loss of consciousness. Studies have been conducted in the US to assess medication-induced ailments. Cholestatic hepatitis could be a rare side effect of oxycodone use [13]. A guideline from Food and Drug Administration, USA has recommended the removal of acetaminophen-containing (APAP) prescription medications because of potential hepatotoxicity [63]. APAP, NSAID and prescription opioids are generally recommended for pain alleviation in the US [64]. One hospital-based study in the US has reported one of the major reason of acute liver failure is associated with the use of APAP [65]. Multiple uses of these drugs would lead to hepatotoxicity [66]. However, while assessing the risk of critical cases of hepatotoxicity resulting in hospitalization after use of opioid/acetaminophen combination one study has suggested that there is no population-based data supporting the risk [67].

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One of the most abused and addictive drug is heroin (diacetylmorphine), which is the key psychoactive chemical found in opium. Though an addictive drug, not all users become addicted to it. Morphine leads to euphoria and interacts with the reward pathway in the brain. After crossing the blood-brain-barrier, heroin is converted to morphine. At the μ receptor subtype, morphine acts as a strong agonist. Subsequently there is inhibition of GABA release from nerve terminal leading to attenuated inhibitory effect of GABA on dopaminergic neurons. Therefore there is sustained activation of dopaminergic pathway leading to euphoric responses. Morphine can be administered in multiple ways including oral, subcutaneous, sublingual, intramuscular or intravenous. Peak plasma levels of morphine varies by the route of administration [68]. Morphine metabolism into morphine3-glucuronide and morphine-6-glucuronide can take place in liver, brain and kidney [69, 70]. A review has indicated the potential of generating hepatotoxicity after long-term use of naltrexone [71].

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ACCEPTED MANUSCRIPT 3.4.1. Research findings 3.4.1.1. In vitro studies Cultured human hepatocytes has been used to determine the hepatotoxicity of various opioids including heroin [72]. The study suggested that heroin would not induce irreversible damage to human hepatocytes when administered at therapeutic doses [72]. Similarly, heroin hepatotoxic study was performed in the presence of ethanol [73].

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3.4.1.2. In vivo studies

Overdose of buprenorphine could potentially cause hepatitis [74].When administered to mice, buprenorphine lead to attenuated ATP formation and impaired mitochondrial respiration [74]. 3.4.1.3. Clinical studies: Human/Patient

3.5. Nicotine

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Heroin poisoning is usually suspected in all comatose patients because different level of purity of heroin has been associated with fatal heroin overdose [75]. Medical conditions and consumption of other drugs including alcohol enhances the risk of fatality from heroin overdose [76]. Usually, respiratory depression and coma are the key outcomes of opioid overdose [77]. Half-maximal cytotoxic concentration of heroin got reduced for human hepatocytes by pre-exposure to ethanol and the enhanced toxicity was associated with increase in cytochrome P-450 levels of the pretreated hepatocytes [73]. How heroin addiction leads to vascular hepatitis has been studied. Drug abusers had a deposit of fibrotic matrix in the terminal hepatic vein wall [78]. Perisinusoidal fibrosis and perivenular fibrosis were more frequent along with reduced venular wall cellularity in ex-drug abusers [78]. To treat heroin addicts buprenorphine is used to sublingually [79]. In latent hepatitis C patients suffering from heroin addiction, therapeutic dose of buprenorphine could lead to acute liver failure by mitochondrial toxicity [80, 81]. Heroin addiction is also treated by naltrexone, a specific opiate receptor antagonist. Chronic naltrexone administration for 3 years did not alter liver function as assessed by serum transaminase levels [82].

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One of the most addictive substances, nicotine comes from tobacco leaves which contain a lot of chemicals that can also cause cancer. Even though smoking is prevalent more in men than women the ratio is getting changed a bit [83]. The number of cigarette smoked has crossed the 6 trillion mark [84]. In spite of increased awareness, the expected number of smokers will be close to 2 billion [83]. Both smoking and smokeless tobacco harm us. According to National Institutes of Health, USA nicotine can have various effects on our body including decreased appetite, elevated heart rate and blood pressure, and increased saliva and phlegm. Tobacco smoking leads to reduced pulmonary capacity as evidenced by wheezing, cough, and damage to lungs [85]. Smoking is also associated with increased blood pressure and narrow blood vessels [86]. Smokers depend on nicotine to feel normal [87]. Day-to-day stress level is influenced by smoking [88]. Absorption of nicotine occurs via the skin, lungs and respiratory tract [89]. Metabolism of nicotine mainly occurs in liver. The withdrawal symptom of nicotine starts 2-3 hours after the last use of tobacco. Nicotine withdrawal symptoms include anxiety, depression, drowsiness, headache, and increased weight gain.

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ACCEPTED MANUSCRIPT 3.5.1. Research findings 3.5.1.1. In vitro studies

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Few studies have been demonstrated that investigated the effects of nicotine in vitro. Nicotine exposure affects osteoblast proliferation, metabolism, extracellular matrix formation and growth factor signalling cascade including FGF-1, FGF-2, and RUNX2 [90, 91]. Interestingly, using hepatic cell line HepaRG, it has been demonstrated that nicotine administration leads to dose-dependent reduction in NNK-induced DNA double strand break [92]. When administered on HaCaT cells and A549 cells, electronic cigarette vapour caused some toxic effects on cell viability [93]. 3.5.1.2. In vivo studies

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Too much use of nicotine results in nicotine poisoning. Not surprisingly a lot of in vivo studies have been performed to understand nicotine-mediated liver injury. Nicotine induces haematological and reproductive toxicity in rats [89]. Nicotine has been suggested to be a key player in NADPH oxidasemediated cytotoxicity [94]. Several studies have investigated the role of nicotine in liver function. When male mice were treated with acute or subchronic doses of nicotine hydrochloride, no obvious difference was observed in the level of SGPT and SGOT [95]. When rats are exposed to chronic low dose of nicotine pre- and post-natally, there were behavioral changes in the adults and the new born [96]. Female rats suffered from pancreatic disruptions after administration of cigarette smoking residues sub-cutaneously [97]. Nicotine administered orally to rats resulted in reduced porosity of the liver due to reduced diameter [98]. Effect of nicotine’s interaction with CCl4 in rat liver has been investigated [99]. High nicotine dose administered in rats did not alter thyroid function with unchanged serum T3, T4, and TSH concentrations [100]. 5'-deiodinase activity also remained unaltered after nicotine administration [100]. Poly-aromatic hydrocarbons, preferentially induced by cytochrome P-450 1A1 are responsible for tobacco smoke exposure-mediated lung cancer susceptibility. Nicotine fed orally to rats lead to dose-dependent induction of CYP1A1 activity in liver, kidney and lung and CYP1A2 induction in the liver [101]. CYP2E1 is induced by tobacco smoke in animal models [102]. Pharmacological dose of nicotine also enhances the level of CYP2E1 protein activity in rat liver [103]. Peak level of CYP2E1 is observed after nicotine treatment; however, one exposure of nicotine may not be sufficient to cause CYP2E1-mediated hepatotoxicity [104]. Prenatal exposure of 108μM nicotine enhances the focal necrosis in rat pups [105]. Post-natal nicotine exposure to pups without prior exposure also increases focal and confluent necrosis [105]. Malondialdehyde level though unaffected at birth was increased after prenatal nicotine exposure [105]. Curcumin and its analog has modulatory activity on circulatory lipid profile in rats having nicotine-induced toxicity [106]. Melatonin, quercetin and hesperidin alleviated the effect of nicotine toxicity to liver [90-94]. Gender may also be a critical factor that could indicate the level of oxidative stress after nicotine exposure [107]. Maternal nicotine exposure during lactation period leads to induced oxidative stress in liver and lung of lactating offspring especially in male rats [107]. Level of malondialdehyde was increased, while thiol concentration was reduced after nicotine exposure [107]. Female albino rats administered nicotine subcutaneously demonstrates extensive DNA damage and hepatic cell death possible by up-regulation of pro-apoptotic proteins [108]. Expression of p65, Bcl-2 and Bax were induced post nicotine treatment [108]. Serum TNF-α, and IL-6 levels were also increased after nicotine exposure [108]. Study in rats suggests that nicotine metabolism is not

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ACCEPTED MANUSCRIPT influenced by alcohol addiction [109]. The level of proliferating cell nuclear antigen, an S-phase marker was higher in male hepatic tissues than female tissues in addicted rats [109]. 3.5.1.3. Clinical studies A recent study has compared the toxic and carcinogenic metabolites between electronic-cigarette and traditional cigarette smokers [93, 110]. Whether prenatal nicotine exposure causes attention deficit hyperactivity disorder is not completely understood [111].

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3.6. Methadone

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Methadone is an example of another opioid drug used as a pain reliever. Methadone also attenuates withdrawal symptoms from people suffering from heroin or other narcotic drug addiction. Methadone is not prescribed to take if someone suffers from severe asthma. According to FDA, methadone is classified as pregnancy category C, which suggests it is unknown whether methadone will harm an unborn baby. Methadone also acts by binding to μ-opioid receptor. It can also acts as strong non-competitive α3β4 nicotinic acetylcholine receptor antagonist in rat receptors [112]. Methadone metabolism rates alter greatly among individuals [113]. Rate of metabolism also affects the required dose of methadone used to alleviate pain [113]. In clinic, methadone is administered in oral solution [113]. Overdose of methadone leads to a variety of symptoms including flushing, nausea, sleepiness, hallucinations, vomiting, headache, increased heartbeat, and abnormal heart rhythms. Withdrawal of methadone causes a lot of physical symptoms including light-headedness, pupil dilation, nausea, fever, sweat, chills and fast heartbeat. Severe methadone toxicity is demonstrated by the following early signs: euphoria, slurry speech and ataxia [114]. Late signs include passing out, loud snoring, emanation of brown pulmonary edema fluid from nose or mouth [114]. Very high dose of methadone has been associated with abnormal heart rhythm that can lead to sudden cardiac death [115]. A case file study has suggested that methadone can increase QTc interval that makes methadone users vulnerable to malignant cardiac arrhythmias [116]. Methadone toxicity-induced death was associated with renal failure while respiratory failure was the leading cause of death [117]. When methadone is consumed along with other drugs it becomes hard to ascertain whether methadone overdose is the lead cause of death [118]. One patient has shown methadone-induced leukoencephalopathy [119]. 3.6.1. Research findings

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A dose of 0.2mM methadone depleted 70% glycogen from cultured hepatocytes while 0.005mM methadone inhibited albumin synthesis by almost 50% [72]. Even though therapeutic methadone does not cause damage to hepatocytes, abuse of the drug can cause liver damage [72]. When hepatocytes are cultured in the presence of adenosyl-L-methionine, it reduces GSH depletion of the cells when incubated with toxic dose of methadone [120]. Pre-treated hepatocytes with ethanol when exposed to methadone showed a reduction of half-maximal cytotoxic concentration of methadone [73]. Increased methadone toxicity by ethanol was associated with reduced intracellular level of GSH and augmented cytochrome P450 level [73]. 3.6.1.2. In vivo studies A few studies have investigated hepatotoxicity of methadone alone or in combination with other drugs. One of such studies demonstrated when desipramine, an antidepressant was administered in 16

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rats it reduced the LD50 of methadone [121]. A spurt in the level of unchanged methadone in liver was observed after desipramine treatment [121]. Perinatal exposure of methadone has harmful effect on pre-weaning organ and body development of rats as evident from altered dry weight and tissue water content of liver and kidney [122]. When methadone hydrochloride was administered to female guinea it did not alter the level of liver p-nitroanisole O-demethylase (OD), aniline hydroxylase (AH) level but caused a significant reduction in glucuronosyltransferase (GT) activity [123]. Methadone inhibits CYP2D6 from microsomes prepared from human livers as well as in vivo[124]. 3.6.1.3. Clinical studies

When methadone-toxicity related deaths were investigated in Ontario, Canada it was suggested that methadone toxicity is increased in individuals suffering from cardiac and pulmonary disease [125].

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Cannabis is a generic term used to denote the several psychoactive preparations of the plant Cannabis sativa. The major psychoactive constituent in cannabis is ∆-9 tetrahydrocannabinol (THC). Compounds that are structurally similar to THC are referred to as cannabinoids. It has been demonstrated that, in neurons cannabinoids inhibit adenylcyclase, probably through interaction with an inhibitory G protein. The enzyme would become unable to convert adenosine triphosphate into the 'second messenger' cyclic adenosinemonophosphate (cAMP). Other mechanisms besides this have been proposed including inhibition of calcium channels, activation of potassium channels or the phospholipid-inositol mechanism [112]. 3.7.1. Research findings

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3.8. Fentanyl

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One group had conducted a case study involving 123 patients those who were chronic marijuana users. The study revealed that on its own or in association with other drugs, cannabis was associated with hepatic morphologic and enzymatic alterations. This indicates that cannabinoids are possible hepatotoxic substances [126].

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Another strong opioid drug and powerful than morphine or heroin, fentanyl is used to treat patients who have severe pain or to alleviate post-surgery pain as well as anaesthetic agent. Fentanyl belongs to the phenylpiperidine class of drugs. The drug is also used to treat people who are tolerant to opioids. Fentanyl binds to the opioid receptors that control pain and emotions. The drug can be absorbed into the body via inhalation, oral exposure or ingestion, or skin contact. Not surprisingly fentanyl has its own side effects including difficulty in breathing, hives, swelling of face, slow heartrate, and muscle stiffness. 3.8.1. Research findings 3.8.1.1. In vitro studies Suspended rat liver cells were treated with different drugs including fentanyl to assess hepatotoxicity using enzyme leakage, cell viability, intracellular ATP content [127]. When compared with the known in vivo effects of the drugs, fentanyl did not demonstrate any discrepancy [127]. 17

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Toxicity studies of anaesthetics have been conducted more than three decades back. When administered into rats, fentanyl cased hepatic injuries similar to other anaesthetic agents including halothane, isoflurane [128]. The same group investigated the effect of oxygen concentration, hypothermia and choice of vendor on anaesthesia-induced hepatic injury in rats [129]. It was shown that halothane caused hepatic injury in 12% and 14% oxygen while fentanyl and other anaesthetic agents caused more hepatic injury in 10% oxygen exposure [129]. The effect of fentanyl on hepatic function in cirrhotic rats were assessed [130]. Cirrhotic rats were exposed to CCl4 inhalation followed by treatment with fentanyl or other volatile anaesthetics. Fentanyl treatment did not produce respiratory acidosis and alteration in serum glucose level but there was moderate increase in SGPT and SGOT levels in both cirrhotic and non-cirrhotic rats [130]. Fentanyl does not provide any protective effect against chemical-induced hepatotoxicity that were assessed by measuring liver enzymes in serum, enlarged liver and vacuolar degeneration of hepatocytes [131]. The effects of the drug has also been assessed not only in rodents but also in dogs [132]. When fentanyl was administered in ethanol-treated dogs, the content of cytochrome P450 was increased drastically [132]. Fentanyl in combination with another anaesthetic, droperidol did not significantly increase hepatocellular enzyme release and circulating lactate after ischemia-repurfusion in rabbits [133]. 3.8.1.3. Clinical studies

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The safety of fentanyl has been studied in humans. To address the pain management of patients suffering from renal or hepatic disorder it has been demonstrated that fentanyl provides safe pharmacological profile [80]. This has been supported by another study looking into patients with hepatic impairment [134]. The pharmacokinetics of fentanyl remains unaltered in hepatic disease patients [134]. When hepatocellular carcinoma patients underwent radiofrequency ablation sustained administration of fentanyl proved to be a safe analgesic compared to one-shot intravenous delivery [135]. 3.9. Meperidine

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Meperidine or pethidine is another opioid analgesic that belongs to phenylpiperidine class [136]. Thought to be a potential anticholinergic agent, meperidine was used to treat moderate to severe pain [137]. Even though the use of meperidine was prevalent owing to its safety and less chance of addiction profile, it was later discovered that the drug has its fair share of addiction issues as well as toxic effects [136]. Meperidine acts as agonist at the μ opioid receptor. Meperidine is hydrolyzed in the liver to pethidinic acid; conversely the drug can also be methylated to toxic norpethidine. One of the known metabolite of meperidine is normeperedine. 3.9.1. Research findings 3.9.1.1. In vitro studies

When cultured human hepatocytes were treated with meperidine, glycogen content was reduced [72]. There was reduction in albumin synthesis as well as in the level of intracellular glutathione at a dose which was not therapeutic [72]. 3.9.1.2. In vivo studies Most of the studies pertaining to meperidine toxicity has been ascertained in human. One study has looked into the effect of meperidine in vivo. Route of administration does play a role in the effect of 18

ACCEPTED MANUSCRIPT these analgesics. When administered systemically in ICR mice, meperidine reduced hepatic GSH concentrations [138]. However, when administered intracerebroventricular process, meperidine did not attenuate GSH concentration in hepatocytes [138]. This phenomenon could also be explained by the fact that hepatic metabolisms of some opioid are required for their activity in the CNS. 3.9.1.3. Clinical studies

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While assessing the metabolism of meperidine to normeperidine in normal and cirrhosis patients, serum concentration and urine excretion of meperidine and normeperidine was measured [139]. Patients suffering from cirrhosis had less systemic clearance of meperidine and increased bioavailability and half-life than normal patients suggesting that patients who need sustained meperidine should take the drug parenterally to have the maximal analgesic effect compared to the oral route [139]. Traumatic injury can change hepatic function that can be assessed by measuring the changes in hepatic microsomal activity, hepatic blood flow rate. While performing pharmacokinetic studies in traumatic patients, meperidine clearance was measured [140]. The study suggested that ideal body weight could be used as a guide to select meperidine dose in the trauma patients [140]. In trauma patients the concentration of α1 acid glycoprotein, an acute phase reactant protein that binds to meperidine was increased after the trauma [140]. Another study compared the metabolism and hepatic function of enflurane and meperidine compared with single dose of halothane in humans [141]. Liver histology, post-operative liver function tests, intraoperative indocyanine green clearance was measured in patients undergoing abdominal surgery. Urinary fluoride excretion was increased post-anaesthesia in the enflurane group only while no difference between the pre- and postoperative disposition of antipyrine was observed between enflurane and meperidine groups [141]. However, antipyrine clearance was reduced significantly in the halothane group after anaesthesia [141]. Serum ALT and bilirubin concentrations were significantly elevated after surgery in halothane and enflurane groups that was similar in pre-surgery meperidine patients [141]. It has been suggested that hepatic disorder patients should refrain from taking multiple meperidine doses owing to CNS excitatory toxicity and slower elimination of the metabolites [134, 142].

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Hydromorphone or dihydromorphinone is another opioid class analgesic drug. The drug is another μopioid agonist and ketone form of morphine. Hydromorphone has a better ability to cross the bloodbrain barrier and faster access to CNS. Prescription hydromorphone is known as Dilaudid, Dimorphone, Hydal and others. Hydromorphone adverse effects are similar to that of morphine and heroin that include respiratory ailments while the side effects include dizziness, nausea, vomiting, sedation and sweating. 3.10.1. Research findings 3.10.1.1. In vitro studies Rat hepatocytes were cultured and exposed to morphine, normorphine and morphinone to assess the hepatotoxicity. Morphinone-induced cytotoxicity was higher than morphine as was correlated with the decrease in the level of intracellular glutathione [143].

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Naltrexone, an opioid antagonist (in response to hydromorphone and cocaine) has been suggested to be useful for treating patients with concurrent cocaine and heroin abuse [145]. Since liver transplant patients undergo extensive liver extension, the effect of epidural infusion consisting of hydromorphone was assessed in these patients [146]. The infusion did not cause any neurologic injury or local anaesthetic toxicity [146]. However, hydromorphone should be used with caution because of altered parent drug clearance and also accumulation of toxic metabolites [80, 134]. 3.11. Chemotherapeutic drugs

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Chemotherapeutic drugs related liver injury can cause morbidity and mortality. Since DILI caused by chemotherapy is idiosyncratic in nature it is difficult to predict the injury. Causing direct hepatotoxicity and exacerbating existing liver disease are the two major ways chemotherapeutic drugs cause liver injury. The clinical spectrum of hepatotoxicity induced by chemotherapy varies from jaundice to advanced fibrosis finally leading to fulminant hepatic failure. Adding to the complexity is that natural history of chemotherapy-induced liver injury is also variable. A report from the US suggests that only 4% of the total DILI cases is chemotherapy-induced which did not lead to mortality [147]. Multiple factors regulate the clinical manifestation of chemotherapy-induced DILI. They include age, sex, genetic susceptibility, pre-existing liver disease, medications and inept immune system [148]. 3.11.1 Clinical Research findings

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Chemotherapy-induced hepatotoxicity can be caused by hepatocellular injury or cholestasis. Preexisting liver conditions including steatosis lead to improper innate immunity thereby enhancing the susceptibility to liver injury. Chemotherapy can lead to injury to sinusoidal epithelial cells causing thickening subsequently resulting in sinusoidal obstruction syndrome (SOS)[149]. Patients following oxaliplatin or irinotecan-based chemotherapy along with 5-fulorouracil regimen have enhanced prevalence of SOS [150]. Even radiation-based liver injury bears the signature histopathological features of SOS. There are multiple cytotoxic drugs that lead to DILI. Alkylating agents such as cyclophosphamide and ifosfamide have been associated with DILI. Cyclophosphamide might be responsible for idiosyncratic DILI, while attenuated dose is not critical in ifosfamide-mediated liver injury [151]. Antimetabolites such as 6-mercaptopurine, a purine analogue and azathioprine, a 6-mercaptopurine derivative have been implicated in liver injury [152, 153]. High dose of methotrexate enhances the level of transaminases [154]. Vincristine and vinorelbine, both vinca alkaloids have been associated with improper liver enzyme functions. Modified dose is suggested for patients suffering from hepatic dysfunction [155, 156]. Various tyrosine kinase inhibitors hold the key to treat specific cancers. However, some of these inhibitors including sunitinib, ponatinib, lapatinib, regorafenib and pazopanib have warning labels of 20

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potential hepatotoxicity. Sunitinib, a multikinase inhibitor has been associated with hepatotoxicity and drug discontinuation has been suggested based on the serum transaminase and bilirubin level [22]. Ponatinib, specific for refractory CML should not be used in patients having hepatic impairment [22]. Dose reduction of lapatinib, a drug approved for metastatic breast cancer is recommended in patients with mild hepatic impairment [22]. Regorafenib is approved for metastatic colorectal cancer; however, liver enzymes are monitored when the drug is used [22]. Pazopanib, approved for metastatic renal cancer and soft tissue carcinoma can lead to augmented ALT and bilirubin level [157]. Monoclonal antibodies have been targeted to treat cancer. Ipilimumab, approved for treating advanced melanoma can lead to increased hepatotoxicity when used in combination with dacarbazine[158]. Nodular regenerative hyperplasia has been reported with trastuzumab, an antibody-drug conjugate [159]. Bevacizumab that targets VEGF results in enhanced ALT level when combined with fluorouracil and irinotecan. Taxanes such as paclitaxel and docetaxel have been associated with moderate elevation of aminotransferases in the context of medications metabolized by cytochrome p450 [160]. Ixabepilone, is another taxane whose dose modification is recommended [22]. Immunotherapy has been explored as a mean to treat cancer. IL-2 which stimulates Kupffer cells and induces sinusoidal endothelial damage could lead to severe cholestasis [161]. Pegylated IFN-α might lead to autoimmune liver injury when used as adjuvant chemotherapy to treat melanoma [162]. 4. Cytokine modulation in drug-induced liver injury

Cytokine Modulation Cocaine increased TNFα gene expression in mouse livers [165, 166]. The study of proliferation of hepatic lineage cells of normal C57BL/6 and interleukin-6 knockout mice after cocaine-induced periportal injury showed that the proliferative response in IL-6 knockout mice shows that IL-6 is not required for proliferation of liver cells [167]. Attenuated plasma IL-10 level when compared to social drinkers, increased TNF-α level when exposed to stress [168]. Decreased TNF-α, CCL2, CXCL12, SDF-1 in cocaine users; Increased IL-1β in users with psychiatric disorders [169]. Acute administration of 3,4-methylenedioxymethamphetamine (MDMA) induces TNFα-mediated apoptosis in rat liver [52]. Methamphetamine administration modifies leukocyte proliferation and cytokine production in murine liver tissues [170]. Increased IL-4 and reduced IL-10 in mice lung explants after amphetamine treatment [171]. Inhibits IL-6 production by IL-2 activated PBMCs [172].

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Drug Cocaine

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Cytokine levels have been altered during drug-induced liver injury. NK cells, and NKT cells are predominant lymphocytes in liver [163]. One such study has reported that the cytokine IL-30 can be used as therapeutic since it can attenuate liver fibrosis where NKT cells play a very important role [164]. In table 2 we have highlighted altered cytokine expression level affected by the use of various drugs of abuse causing liver injury. Some of these drugs would show contradictory effects on specific cytokines depending on the species examined either in vitro or in vivo.

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Nicotine

Inactivation of the basolateral amygdala blocks the suppressive effect of heroinassociated environmental stimuli on iNOS induction and on the expression of the pro-inflammatory cytokines TNF-α and IL-1β in spleen and liver tissue [173]. HIV-infected heroin users demonstrate reduced IL-1β, IL-6, IFN-α, IL-10 after LPS activation [174]. Splenocytes from heroin treated mice show increased level of IL-1β, IL-2, TNF-α and IFN-γ [175]. Transdermal nicotine administration reduces the posttraumatic increased cytokine TNF-α, IL-1β, and IL-6 levels in the heart and liver homogenates [176]. intracerebroventricular injection of nicotine activates hepatic and splenic IL-6 mRNA expression and plasma IL-6 levels in mice [177]. Smoking increases the production of pro-inflammatory cytokines (IL-1, IL-6, and IL13 and TNF- α) [178]. Nicotine could attenuate the mRNA expression of IL-6, IL-1β and TNF-α in poly (I:C) stimulated peritoneal macrophages; and suppress the production of IL-6 and TNF-α from poly (I:C) stimulated macrophages [179]. Attenuate production of IL-2, TNF, and IFN-γ in response to anti-CD3 stimulation in human PBMC [180]. Down-regulation of TNF release and cytokine mRNA expression in murine alveolar macrophage cell line [181]. Inhibition of IL-10 production by human non-adherent mononuclear cells, no effect on IL-2 and TNF-α [182]. Methadone and buprenorphine significantly depresse cytokine levels [183]. Reduced IL-2 production by murine splenocytes [184]. Th1/Th2 cytokine balance in heroin addicted subjects [185]. Serum levels of IL-6, TNF-α, TGF-β1 has been changed [186]. Inhibited expression of IL-1α, IL-1β, IL-6 and TNF-α in cultured rat microglial cells [187]. Cannabinoid CP55, 940 induces TNF-α, IL-8, MCP-1 in human promyelocytic cell line HL-60 [188]. Inhibit the expression of TNF-α, IL-6 and IL-10 in human whole blood [189]. Reduced serum IL-10 and TNF-α in septic mice [190]. Did not affect human mast cell degranulation [191]. 5-FU inhibited TNF-α, IL-1, and IL-6 in serum of rats having pancreatitis [192]. 6-MP increased cytokine-induced release of G-CSF, M-CSF and GM-CSF [193]. Bevacizumab attenuates serum IL-6, IL-8 and IL-10 in colorectal cancer patients [194]. Imatinib augments IL-6 production by hepatic stellate cells [195]. Oxaliplatin may induce huge release of IL-6 and TNF-α in colorectal cancer patients [196].

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Table 2: Altered cytokine levels mediated by drugs of abuse and addiction

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5. Conclusion In this article, we have focused the mechanistic aspect involved in liver injury induced by eleven important drugs of abuse and addiction: Cocaine, Amphetamine, Oxycodone, Heroin, Nicotine, Methadone, Cannabis/Marijuana, Fentanyl, Meperidine, Hydromorphone and Chemotherapeutic drugs. Interestingly, these drugs have been started using by the abusers for the purpose of addiction long time back but the awareness of toxicity is not up to the mark. It is well-known that these drugs have severe consequences in major organs of the body including liver. Most of these drugs follow the universal process of toxicity development in liver, which have been established by various research groups. We have noticed a gap where scientists have the scope to spell out the mechansism of hepatocyte death including pointing out the intrinsic or extrinsic pathways involved. The drugs of abuse and addiction may cause liver injury in several ways, but three main categorical types have been observed in the published research articles available in ‘pubmed’, those are usually referred as dose-dependent (or intrinsic) toxicity, dose-independent (or idiosyncratic metabolic) toxicity and drug allergy (or idiosyncratic immunological) (Fig 1). The liver has a central role as a detoxifying organ towards xenobiotics and chemicals. However, biotransformation to less toxic substances can actually involve production of molecules that can induce liver injury through various pathways. Important mechanisms involved in drug-induced hepatic injury can be divided into: (1) reactive metabolite formation via metabolism, (2) covalent binding between cellular components with drug, (3) reactive oxygen species generation in the cells, (4) activation of signal transduction pathways that modulate cell death or survival and (5) cellular mitochondrial damage [197]. Once the main principles of injury of liver is discontinued, the liver can be renewed and become fully functional again as it has the regeneration capacity to recover from the damage, even full recovery is also possible from extensive hepatocyte death [197].

Figure1: Schematic diagram of liver injury by illicit drug

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In conclusion, numerous mechanisms that could potentially be targeted to discover the drug against basic addiction in neuroscience aspect, but clinical translation remains a challenge. The initial therapeutics approach that targets these mechanisms will require a considerable investment, at a time when the willingness of the pharmaceutical industry to invest in drug development for behavioural disorders has reduced. We accept that these challenges should initiate some rethinking in academic institutions, industry, and government in approach to the development of medications for addictive disorders.

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The authors declare no conflict of interest.

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ACCEPTED MANUSCRIPT Research Highlights 1. Liver function indicates the magnitude of liver damage of drug addicted individual. 2. Risk factors, symptoms and pathogenesis of liver are already studied by clinicians. 3. Zonal necrosis is observed in liver caused by DILI.

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5. Cytokines are modulated by the drugs of abuse and addiction.

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4. Alteration of morphology and function of mitochondria is identified in hepatocytes.

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Dr. Goswami has nothing to disclose,

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