Pharmacology and metabolism of alcohol, including its metabolic effects and interactions with other drugs

Pharmacology and Metabolism of Alcohol, Including Its Metabolic Effects and Interactions With Other Drugs CHARLES S. LIEBER, MD CHAIM S. ABITTAN, MD

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lcohol is a small molecule that is both water and lipid soluble. Therefore, it readily permeates all organs of the body and affects many of their vital functions.1 The most important ones, the likely mechanisms, as well as associated alcohol-drug interactions will be reviewed, with only brief mention of the classic, well-documented cutaneous signs of alcoholism and some newer emerging associations, which are discussed in detail elsewhere in this issue.

Metabolism of Ethanol and Associated Metabolic Disturbances Ethanol is readily absorbed from the gastrointestinal tract. Only 2–10% of that absorbed is eliminated through the kidneys and lungs; the rest is oxidized in the body. There are three known enzyme systems that oxidize ethanol: alcohol dehydrogenase (ADH), the microsomal ethanol oxidizing system (MEOS), and catalase. Through each of its three pathways, ethanol produces specific metabolic and toxic disturbances. All three convert ethanol to acetaldehyde, a toxic breakdown product of alcohol, which is converted in turn to acetate by aldehyde dehydrogenase. Most tissues of the body contain enzymes capable of ethanol oxidation or, at least, non-oxidative metabolism, but significant activity occurs only in the liver and, to a lesser extent, in the stomach. Hence, medical consequences are predominant in these organs. Indeed, many of the metabolic and toxic effects of alcohol in the liver have been linked to its metabolism in that tissue. This relative organ specificity, coupled with the high energy content of ethanol (each gram provides 29 kJ, or 7.1 kcal) and the lack of effective feedback control of its rate of metabolism, may result in a displacement, by ethanol, of up to 90% of the liver’s normal metabolic substrates and probably explains why ethanol disposal produces strikFrom the Bronx VA Medical Center and Mount Sinai School of Medicine, New York, New York. Address correspondence to Charles Lieber, MD, V.A. Medical Center (151-2), 130 West Kingsbridge Road, Bronx, NY 10468. © 1999 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

ing metabolic imbalances in the liver. The extent to which ethanol becomes the preferred fuel for the total body has been demonstrated in humans: It decreased total body fat oxidation by 79% and protein oxidation by 39%, and it almost completely abolished the rise in carbohydrate oxidation seen after glucose infusion.2

Oxidation of Ethanol in the Stomach: Gender and Ethnic Differences Alcohol has been known to disappear from the stomach and this was considered to be part of its “absorption” from the gastrointestinal tract. It was quantitated postprandially by Cortot et al3 in seven healthy subjects. They found that, of the ingested alcohol, 39.4 ⫾ 4.1% was absorbed through the stomach wall during the first postprandial hour and 73.2 ⫾ 4.2% during the total time. It is now apparent that some of this absorbed ethanol is actually metabolized in the gastric wall. As a result, when alcohol is taken orally, blood levels achieved are generally lower than those obtained after administration of the same dose intravenously,4,5 the so-called first-pass metabolism (FPM). Many drugs undergo FPM, which usually reflects metabolism in the liver. The gastric mucosa also contains several enzymes with alcohol dehydrogenase activity,6 one of which is a class IV ADH (called sigma-ADH) and is not present in the liver. This enzyme has now been purified,7 its fulllength cDNA obtained and the complete amino acid sequence deduced.8 Furthermore, the gene (ADH7) was cloned,9,10 and localized to chromosome 4.11 The upstream structure of human ADH7 gene and the organ distribution of its expression were also defined.12 Sigma-ADH was found to have a high capacity for ethanol oxidation, greater than that of the other isozymes. Its affinity for ethanol is relatively low, with a Km of about 30 mM,7 but this is not a drawback in the stomach where ethanol is commonly present at much higher concentrations. In vitro, gastric ADH was found to be responsible for a large part of ethanol metabolism observed in cultured rat13 and human14 gastric cells. The in vivo relative 0738-081X/99/$–see front matter PII S0738-081X(99)00020-6

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contribution of gastric and hepatic ADH to ethanol metabolism is still the subject of debate,15–18 but studies by other researchers19 showed true gastric FPM in experiments using the same dose of alcohol given by either intragastric intubation or by intravenous, intraportal, and intraduodenal infusions at a rate that mimicked the loss of alcohol from the stomach. Furthermore, rats that had developed portosystemic shunts after ligation of the portal vein exhibited blood alcohol curves and FPM equivalent to those of sham-operated controls, indicating again that FPM is not dependent on first-pass flow through the liver but reflects, at least in part, gastric metabolism.19 The concept of ethanol metabolism in the stomach was also supported indirectly by the observation that commonly used drugs, such as aspirin,20 and some H2blockers,6,21 which decrease the activity of gastric ADH6,13,14,21,22 and/or accelerate gastric emptying,23 also increased blood alcohol levels in vivo. This was particularly apparent after repeated intake of low alcohol doses, mimicking social drinking.24 Although questioned at first, such increases in blood levels have now been confirmed25,26 for low ethanol doses. The blood level achieved by each single administration of such low doses is small, but social drinking is usually characterized by repetitive consumption of small doses. Under those conditions, the effect of the drug is cumulative,24 and the increase in blood alcohol becomes sufficient to reach levels known to impair cognitive and fine motor functions.27–29 Some ethnic differences also support the concept of the role of gastric ADH in FPM of ethanol. Indeed, ␴-ADH is absent or markedly decreased in activity in a large percentage of Japanese subjects.30 Their FPM is reduced correspondingly,31 in keeping with a predominant role for ␴-ADH in human FPM. Thus, the FPM represents a kind of “protective barrier” against the systemic effects of ethanol, and its stimulation was invoked to explain some associated attenuation of liver damage.32,33 Gender differences have also been described: Women have a greater vulnerability than do men to the development of organ damage after chronic alcoholic abuse, both in terms of liver disease34 –37 and brain damage.38 It is noteworthy that in Caucasians, gastric ADH activity is lower in women than in men,39 at least below the age of 50,40 a difference mainly due to lower ␹-ADH activity in women than in men.41 This was associated with higher blood alcohol levels, an effect more striking in alcoholic than in nonalcoholic women39 because FPM is partly lost in the alcoholic,42 together with decreased gastric ADH activity. Furthermore, in women, the alcohol consumed is distributed in a 12% smaller water space39 because of a difference in body composition (more fat and less water). The larger proportion of ethanol that enters the systemic circulation in women

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than in men may contribute to their greater vulnerability to alcohol, not only in terms of central nervous system manifestations but also for liver disease, especially as women have less effective defense mechanisms against alcoholic liver injury.43 The magnitude of FPM also depends on the concentration of the alcoholic beverages used. Indeed, gastric ADH isozymes require a relatively high ethanol concentration for optimal activity (vide supra). Therefore, the concentration of alcoholic beverages affects the amount metabolized,44 with lesser FPM and higher blood levels after beer than whiskey45 for equivalent amounts of ethanol. Fasting also strikingly decreases FPM,42 most likely because of accelerated gastric emptying, resulting in shortened exposure of ethanol to gastric ADH, and its more rapid intestinal absorption. When alcohol is being metabolized in the stomach, it is converted to its toxic metabolite acetaldehyde, and some resulting gastric injury can be expected. It is possible, of course, that alternatively, or in addition, alcohol may favor gastric injury in some other ways. For instance, the alcohol (or acetaldehyde)-induced mucosal injury may, in turn, promote implantation or persistence of Helicobacter pylori (HP) in the stomach. An increased incidence of HP infection in the alcoholic has been observed.46 As both ethanol and the ammonia (NH3) generated by HP activate cysteine proteases,47 they also could potentiate each other’s gastric toxicity and play a role in the pathogenesis of gastritis.48 Indeed, gastric NH3 (and hence HP) can be eliminated with antibiotics49,50 and, with the eradication of HP, chronic gastritis usually resolves.51

Hepatic Metabolism of Ethanol and Its Consequences The ADH pathway and associated metabolic disorders ADH ISOZYMES Alcohol dehydrogenase is the liver’s major pathway for ethanol disposition. The raison d’eˆtre of ADH might be to rid the body of the small amounts of alcohol produced by fermentation in the gut.52 Also, ADH has a broad substrate specificity, which includes dehydrogenation of steroids, oxidation of the intermediary alcohols of the shunt pathway of mevalonate metabolism, and ␻-oxidation of fatty acids;53 these substrates may provide a “physiologic” role for ADH. Human liver ADH is a zinc metalloenzyme with five classes of multiple molecular forms that arise from the association of eight different types of subunits, ␣, ␤1, ␤2, ␤3, ␥1, ␥2, ␲, and ␹, into active dimeric molecules. A genetic model accounts for this multiplicity as products of five gene loci, ADH1 through ADH5.54 There are three types of subunits, ␣, ␤, and ␥, in class I. Polymorphism occurs at two loci, ADH2 and ADH3, which encode the ␤ and ␥ subunits. Unlike class I isozymes, which generally have low Km values for ethanol, class II (or ␲) ADH has a relatively high Km (34 mM) and a

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Figure 1. Oxidation of ethanol in the hepatocyte. Many disturbances in intermediary metabolism and toxic effects can be linked to (1) ADH-mediated generation of NADH, (2) the induction of the activity of microsomal enzymes, especially the MEOS containing cytochrome P4502E1 (CYP2E1), and (3) acetaldehyde, the product of ethanol oxidation. GSH, reduced glutathione; GSSG oxidized glutathione. (---) Pathways that are depressed by ethanol; (33) Stimulation or activation, ]- interference or binding. (See Lieber55)

relative insensitivity to 4-methylpyrazole inhibition. Class III (␹-ADH) does not participate in the oxidation of ethanol in the liver because of its very low affinity for that substrate. More recently, a new isoenzyme of ADH has been purified from human stomach (vide supra), socalled ␴- or ␮-ADH (class IV); it is not present in the liver. METABOLIC EFFECTS OF EXCESSIVE ADH-MEDIATED HEPATIC NADH GENERATION In ADH-mediated oxidation of ethanol, acetaldehyde is produced and hydrogen is transferred from ethanol to the cofactor nicotinamide adenine dinucleotide (NAD), which is converted to its reduced form NADH (Fig 1). The formed acetaldehyde again loses hydrogen and is metabolized to acetate, most of which is released into the bloodstream. As a net result, ethanol oxidation generates an excess of reducing equivalents in the liver, primarily as NADH, and it was proposed that the latter may be involved in the hepatotoxicity.56 Indeed, the large amounts of reducing equivalents generated overwhelm the hepatocyte’s ability to maintain redox homeostasis and a number of metabolic disorders ensue, including hypoglycemia, hy-

peruricemia, hyperlactacidemia, and interference with galactose, serotonin, and other amine metabolism.1 Much of alcohol’s derived hydrogen equivalents are transferred into mitochondria by various “shuttle” mechanisms (Fig 1). The activity of the citric acid cycle is depressed, partly because of a slowing of the reactions of the cycle that depend on the NAD/NADH ratio, and the mitochondria will use the hydrogen equivalents originating from ethanol, rather than those derived from the oxidation of fatty acids that normally serve as the main energy source of the liver. This favors hepatic fat accumulation. One of the earliest pathologic manifestation of alcohol abuse is the development of a fatty liver. Fatty acids of different origins can accumulate as triglycerides in the liver because of different metabolic disturbances: decreased hepatic release of lipoproteins, increased mobilization of peripheral fat, enhanced hepatic uptake of circulating lipids, enhanced hepatic lipogenesis, and, most importantly, decreased fatty acid oxidation, whether as a function of the reduced citric acid cycle activity secondary to the altered

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redox potential (vide supra) or as a consequence of alterations in mitochondrial structure and functions.1,57,58 Microsomal ethanol oxidizing system (MEOS) MEOS AND ITS ROLE IN ETHANOL This system was demonstrated in liver microsomes in vitro, and found to be inducible by chronic alcohol feeding in vivo59 and named the microsomal ethanol oxidizing system (MEOS).59,60 The key enzyme in this system is the ethanol-inducible cytochrome P4502E1 (2E1). This enzyme was found to be increased 4 –10 times in liver biopsies of subjects who had recently imbibed alcohol.61 This plays a key role in the metabolic tolerance to alcohol that develops in heavy drinkers. CHARACTERIZATION OF THE

METABOLISM

INCREASED XENOBIOTIC TOXICITY AND CARCINOGENICITY: OXIDATIVE STRESS Much of the medical significance of MEOS (and its ethanol-inducible 2E1) results not only from the oxidation of ethanol but also from the unusual and unique capacity of 2E1 to generate reactive oxygen intermediates, such as superoxide radicals (Figs 1, 2)63,54 and to activate many xenobiotic compounds to their toxic metabolites, often free radicals. This pertains, for instance, to carbon tetrachloride and other industrial solvents such as bromobenzene,65 and vinylidene chloride,66 as well as anesthetics such as enflurane67 and halothane.68 Ethanol also markedly increases the activity of microsomal low Km benzene metabolizing enzymes69 and aggravates the hemopoietic toxicity of benzene. Furthermore, enhanced metabolism (and toxicity) pertains also to a variety of prescribed drugs, including isoniazid and phenylbutazone70 and some over-thecounter medications such as acetaminophen (paracetamol, N-acetyl-p-aminophenol), all of which are substrates of 2E1. Therapeutic amounts of acetaminophen (2.5 to 4 g per day) can cause hepatic injury in alcoholics. In animals given ethanol for long periods, hepatotoxic effects peak after withdrawal71 when ethanol is no longer competing for the microsomal pathway but levels of the toxic metabolites are at their highest. Similarly, alcoholics are most vulnerable to the toxic effects of acetaminophen shortly after cessation of chronic drinking. In fact, such patients hospitalized with acetaminophen toxicity related to accidental misuse had higher rates of morbidity and mortality than did those who attempted suicide, even though the latter had taken more acetaminophen.72 Doxepin, used for controlling moderate pruritus in atopic dermatitis and lichen simplex chronicus, has been shown to result in detectable plasma levels after topical application. This drug is metabolized in the microsomes where it interacts with alcohol. The combination and competition with alcohol may result in enhanced sedative effects and can adversely affect motor skills.73 Many other alcohol– drug interactions have

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been reported,74 too numerous to be described here. The association between alcohol misuse and an increased incidence of upper alimentary and respiratory tract cancers75 is especially noteworthy. Many factors have been incriminated, one of which is the effect of ethanol on enzyme systems involving cytochrome P450-dependent activation of carcinogens. This effect has been demonstrated with the use of microsomes derived from a variety of tissues, including the liver (the principal site of xenobiotic metabolism),76,77 the lungs,76,77 and intestines78,79 (the chief portals of entry for tobacco smoke and dietary carcinogens, respectively), and the esophagus80 (where ethanol consumption is a major risk factor in the development of cancer). Alcoholics are commonly heavy smokers, and a synergistic effect of alcohol consumption and smoking on cancer development has been described, as reviewed elsewhere.75 Indeed, long-term ethanol consumption was found to enhance the mutagenicity of tobacco-derived products.75 Alcohol can also influence carcinogenesis in many other ways,81 one of which involves vitamin A depletion (vide infra). There is increased evidence that ethanol toxicity may be associated with an increased production of reactive oxygen intermediates. Numerous experimental data indicate that free radical mechanisms contribute to ethanol-induced liver injury. Increased generation of oxygen- and ethanol-derived free radicals occur at the microsomal level, especially through the intervention of the ethanol-inducible 2E1 (Fig 1). This induction is associated with proliferation of the endoplasmic reticulum, which is accompanied by increased oxidation of NADPH and resulting H2O2 generation.82 There is also increased superoxide radical production. In addition, the CYP2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury (vide infra). The Catalase Pathway Catalase is capable of oxidizing alcohol in vitro in the presence of an H2O2-generating system83 (Fig 1), and its interaction with H2O2 in the intact liver was demonstrated.84 However, its role is limited by the small amount of H2O2 generated,85 and, under physiological conditions, catalase thus appears to play no major role in ethanol oxidation. Indeed, despite the considerable controversy that originally surrounded this issue, it is now agreed by the principal contenders involved that catalase cannot account for microsomal ethanol oxidation.86,87 However, catalase could contribute to fatty acid oxidation through the following mechanism: Longterm ethanol consumption is associated with increased content of a specific cytochrome (4A1) that promotes microsomal ␻-hydroxylation of fatty acids, which may compensate, at least in part, for the deficit in fatty acid oxidation due to the ethanol-induced injury of the mi-

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tochondria.88 In turn, the products of ␻-oxidation increase liver cytosolic fatty acid-binding protein (LFABPc) content and peroxisomal ␤-oxidation,89 an alternate but modest pathway for fatty acid disposition. Nonoxidative metabolism of ethanol Ethanol can form ethyl esters in vivo, and the corresponding enzyme has been purified.90 Researchers91 found that, compared to controls, in short-term-intoxicated subjects, concentrations of fatty acid ethyl esters were significantly higher in pancreas, liver, heart, and adipose tissue. Because this nonoxidative ethanol metabolism occurs in the organs most commonly injured by alcohol abuse, and because some of these organs lack oxidative ethanol metabolism, these researchers91 postulated that fatty acid ethyl esters may have a role in the production of alcohol-induced injury. This was corroborated by recent evidence for experimental pancreatic damage,92 but further experiments are needed to verify the possible role of this mechanism in the pathogenesis of alcohol-induced injury.

Acetaldehyde Metabolism and Associated Cutaneous Manifestations Toxicity of Acetaldehyde, Including Glutathione (GSH) Depletion and Lipid Peroxidation Acetaldehyde, the active metabolite of ethanol, is the first major specific oxidation product of ethanol by all three of the pathways described. Chronic ethanol consumption results not only in enhanced acetaldehyde production through MEOS induction (vide supra) but also in a significant reduction of the capacity of rat mitochondria to oxidize acetaldehyde.93 Consequently, an imbalance occurs between production and disposition of acetaldehyde, which contributes to elevated acetaldehyde levels.94 Acetaldehyde is released from the liver, travels reversibly bound in plasma and erythrocytes,95 is taken up by extrahepatic tissues, and affects many of them. However, most of the acetaldehyde is normally converted to acetate via aldehyde dehydrogenase (ALDH) in the liver. Acetaldehyde’s toxicity is due, in part, to its capacity to form protein adducts, resulting in antibody production, enzyme inactivation, and decreased DNA repair.96 It is also associated with a striking impairment of the capacity of the liver to utilize oxygen97. Moreover, acetaldehyde promotes GSH depletion, free radical-mediated toxicity, and lipid peroxidation. One of the three amino acids of GSH is cysteine. Binding of acetaldehyde with cysteine and/or GSH may contribute to a depression of liver GSH.98 Acute ethanol administration inhibits GSH synthesis and produces an increased loss from the liver.99 GSH is selectively depleted in the mitochondria100 and may contribute to the striking alcohol-induced alterations of that organelle; also, GSH

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offers one of the mechanisms for the scavenging of toxic-free radicals, as shown in Fig 1 and Fig 2. Although GSH depletion per se may not be sufficient to cause lipid peroxidation, it is generally agreed upon that it favors the peroxidation produced by other factors promoting oxidative stress (vide supra). Therapeutic use of GSH itself is complicated by the fact that its replenishment through supplementation is hampered by its poor penetration into the hepatocytes. Cysteine is one of the three amino acids of GSH, and the ultimate precursor of cysteine is methionine (Fig 2). To be utilized, methionine has to be activated to S-adenosylmethionine (SAMe) (Fig 2), but Duce et al101 found a decrease in SAMe synthetase activity in cirrhotic livers. Consequently, SAMe depletion ensues after chronic ethanol consumption.102 Potentially, such SAMe depletion may have a number of adverse effects. In addition to generating GSH (Fig 2), SAMe is the principal methylating agent in various transmethylation reactions important for nucleic acid and protein synthesis, as well as membrane fluidity and functions, including the transport of metabolites and transmission of signals across membranes and maintenance of membranes. In addition, SAMe plays a key role in the synthesis of polyamines. Thus, depletion of SAMe may promote the membrane injury documented in alcohol-induced liver damage.103 Compared to methionine, administration of SAMe has the advantage of bypassing the deficit in SAMe synthesis (from methionine) referred to above (Fig 2). The usefulness of SAMe administration has been shown in the baboon,102 and in various clinical studies, including the demonstration that it significantly decreases the mortality in patients with alcoholic cirrhosis.104 SAMe is also a methyl donor in the methylation of phosphatidylethanolamine to phosphatidylcholine by the corresponding transferase (PEMT) (Fig 2); however, chronic ethanol consumption is associated with a decrease of this enzyme activity, both in baboons105 and in humans.101 The decrease in PEMT may be responsible, at least in part, for the associated decrease in phospholipids.105,106 Supplementation with polyenylphosphatidylcholine (PPC) was shown to restore the PEMT activity.105 Thus, on the one hand, PEMT depletion after alcohol may exacerbate the hepatic phospholipid depletion and the associated membrane abnormalities, thereby promoting hepatic injury and triggering fibrosis, whereas PPC, by repleting hepatic phospholipids and normalizing PEMT activity, may contribute to the protection against alcoholic cirrhosis provided by its supplementation.88,105,106 Also, PPC acts, in part, by opposing the oxidative stress.107,108 In addition, in cultured stellate cells, PPC prevented acetaldehyde-mediated collagen accumulation,109 at least in part by stimulating collagenase activity; the latter effect was fully reproduced by dilino-

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Figure 2. Link between accelerated acetaldehyde production and increased free radical generation by the induced microsomes, resulting in enhanced lipid peroxidation. Alcoholic liver disease is associated with metabolic blocks between methionine and S-adenosyl-methionine as well as between S-adenosyl-methionine and phosphatidylcholine due to decreases in the corresponding enzyme activities. In addition, B6 deficiency impairs cystathionine production whereas folate and B12 deficiencies slows the conversion of homocysteine to methionine. As discussed in the text, these various defects result in depletion of S-adenosylmethionine, phosphatidylcholine, and GSH and possible accumulation of homocysteine. (See Lieber62)

leoylphosphatidylcholine (DLPC),106 the main phosphatidylcholine species of PPC.

Flushing Flushing may occur in some people after they drink alcohol. It is due to cutaneous vasodilation mediated by acetaldehyde and prostacyclin, a vasodilator.110 Indeed acetaldehyde is a potent stimulant of vascular prostacyclin production and its effect results, at least in part, from enhanced activity of prostacyclin synthetase.110 ALDH has two main isoenzymes, ALDH1 and ALDH2. ALDH2 is responsible for most of the acetaldehyde oxidation to acetate. ALDH2*1 is the normal allele and ALDH2*2 is the abnormal allele, which lacks activity. When ALDH2 activity is decreased, acetaldehyde accumulates in the liver and circulation; this produces the symptoms of flushing, tachycardia, and even circulatory collapse. About 50% of Japanese and Chinese people are deficient in aldehyde dehydrogenase because of inheritance of the ALDH2*2 allele. Homozygotes for this allele (ALDH2*2/2*2) rarely consume ethanol because of the severe side effects of acetaldehyde.111 When they do drink alcohol, these patients tend to develop alcoholic liver disease at a lower cumulative alcohol dose than the control group.112 The ALDH phenotype may be identified by analysis of hair roots113 or by peripheral

blood lymphocyte analysis.114 Furthermore, 94% of those who flush with oral ethanol have a cutaneous response of fast flushing to topical ethanol and acetaldehyde.115 The flushing reaction due to ALDH2 deficiency is mimicked in patients given Antabuse (disulfiram), an inhibitor of the enzyme used for aversive therapy. If these patients imbibe alcohol while taking disulfiram, they develop flushing. The reaction can also include nausea, vomiting, headache, and possibly, convulsions. A number of other drugs that inhibit acetaldehyde metabolism also cause a reaction similar to the one produced by disulfiram. These include griseofulvin, used in the treatment of tinea corporis, tinea pedis, tinea cruris, tinea barbea, tinea capitis, and tinea unguium; and metronidazole, used to treat skin infections caused by Bacteroides sp, Clostridium sp, Peptococcus niger, Peptostreptococcus sp, or Fusobacterium sp; and cephalosporins, which are used in skin infections such as cellulitis.

Mechanisms of Other Cutaneous Manifestations Associated With Alcoholic Liver Disease Jaundice is the most obvious sign in advanced liver disease. It is due to bilirubin staining of the elastic tissue of the skin. Pruritus is the most common associated symptom and is mainly secondary to the presence of bile salts in the skin of patients with obstructive jaundice.116 Sex hormone binding globulin (SHBG), a glycopro-

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tein with a high affinity for binding to testosterone, is produced in the liver. The amount of active (unbound) hormone and thus the ratio of testosterone/estradiol is, in part, dependent on the amount of SHBG in the peripheral circulation.117 In patients with compensated cirrhosis, SHBG is significantly increased; therefore, the free testosterone and the testosterone/SHBG ratio is decreased and the serum estradiol, free estradiol, and the estradiol/testosterone ratio is increased. In addition, because of increased testosterone degradation by the induced liver microsomes, as well as decreased testosterone production (by the testis) and its increased conversion to estrogens,118 the net effect is estrogen excess and loss of androgen stimulation.119 Hyperestrogenemia is associated with telangiectasias, which are expressed in several different ways: Spider angiomata, originally described by Bean,120 resemble the short corkscrew endometrial arteries that slough during the menstrual cycle. They consist of a central arteriole from which numerous small vessels radiate. With pressure on the arteriole, blanching is produced and, when the pressure is removed, the vessels quickly refill from the center. Palmar erythema are diffuse telangiectasias that coalesce and make the hands warm and erythematous. They are most pronounced on the thenar and hypothenar areas, usually sparing the central portion of the palm and are also seen on the plantar surface. On close inspection, the color pulsates and the nails blanche with pressure.121 Paper money skin is the term for diffusely scattered telangiectasias spread in a random manner on the upper trunk and shoulders. They resemble the fine silk threads found in American dollar bills.121 Caput medusae results from dilated veins that radiate out from the umbilicus. They are secondary to increased portal pressure due to cirrhosis of the liver.122 Rhinophyma is statistically associated with alcohol abuse, but the specificity of this sign is low, and most patients with alcoholism do not have it. Its mechanism is unknown.122 Sympathetic neuropathy can develop in chronic alcoholism. This may result in hypohidrosis, which causes the feeling of warm palms.123 Hypoalbuminemia, common in patients with alcoholic liver disease, is considered to be the cause of leuchonychia: Patients first develop multiple white bands (Muehrcke’s lines) in their fingernails and then the entire nail turns white.124 Deficiencies in coagulation factors and platelet dysfunction are also common in alcoholic cirrhosis; therefore, these patients may have easy bruisability and ecchymoses. Porphyria cutanea tarda (PCT) is commonly related to alcohol abuse. Alcohol’s role in this disease is unclear, but it appears to unmask a defect in the uroporphyrinogen decarboxylase, which is involved in porphyrin me-

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tabolism. Liver cirrhosis develops in almost one-third of patients with PCT who also abuse alcohol.125 Sun exposed areas develop vesicles and bullae which later crust over and scar.

Nutritional Deficiencies Associated With Alcohol In addition to causing specific deficiencies in SAMe and phospholipids (vide supra), alcohol abuse has some more general effects on nutrition. Alcohol is rich in energy (29 kJ/g, or 7.1 kcal/g). Thus, a substantial use of alcohol has profound effects on nutritional status.1 It may cause primary malnutrition by displacing other nutrients in the diet because of the high energy content of the alcoholic beverages or because of associated socioeconomic and medical disorders. Secondary malnutrition may result from either maldigestion or malabsorption of nutrients caused by gastrointestinal complications associated with alcoholism, involving especially the pancreas and the small intestine. These effects include malabsorption of thiamine and folate, as well as maldigestion and malabsorption secondary to alcohol-induced pancreatic insufficiency and intestinal lactase deficiency.126 Such primary and secondary malnutrition can affect virtually all nutrients, as described in detail elsewhere.1 Some of these effects have dermatologic impacts, described below. Niacin is an essential component of coenzyme I (NAD) and coenzyme II (NADP), which are key to many biochemical reactions.127 Among other symptoms, niacin deficiency causes pellagra. Areas exposed to sunlight, heat, friction, or pressure develop a redness and superficial scaling resembling a sunburn. When it subsides, it leaves a dusky, brown-red coloration. Vitamin C plays an integral role in collagen and ground substance formation; its deficiency is associated with follicular keratosis with coiled hairs on the upper arms, back, buttocks, and lower extremities and, later, perifollicular hemorrhage with blood pigment discoloration, especially on the legs.128 Zinc is indispensable to the normal functions of all cells of the human body as a cofactor in many enzymatic reactions. Alcoholic cirrhosis is associated with zinc deficiency.129 The clinical manifestations of deficiency include eczema, cheilitis, hair loss, and multiple ungual Beau’s lines (deep transverse depressions on the nail surface due to the arrest of nail growth).122

Interactions of Alcohol With Other Drugs Interactions With the Metabolism and the Effects of Other Drugs Many interactions can occur when alcohol is taken in conjunction with other drugs. These interactions can be (a) antagonistic, so that the effect of either or both agents is blocked or reduced; (b) additive, so that the

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net effect of the combination is the sum of the effects of the individual agents; (c) supra-additive (synergistic or potentiating), so that the effect of the combination is greater than it would be if they were only additive; (d) also, hypersensitivity may be present in alcoholics or heavy drinkers whose alcohol-related pathologies make them especially sensitive to other drugs; and (e) chronic alcohol use also produces tolerance, so that a fixed amount of alcohol has less of an effect than it would in the nonchronic user. It is associated with an induction of the MEOS system, specifically 2E1 (vida supra). There may also be cross-induction of the metabolism of other drugs, in which case a fixed amount of another drug has less of an effect in the alcohol user than in the nonuser. When they are sober, alcoholics may have an increased tolerance to some drugs and, paradoxically, have increased susceptibility to these drugs when intoxicated, because of competition at the level of this enzyme system.130 In addition, some patients have central nervous system tolerance; even with intoxicating levels of circulating ethanol, they appear to be of normal mental status.

Interactions With Drug Absorption and Hepatic Blood Flow: Circadian Rhythm Alcohol consumption can alter drug absorption by delaying gastric emptying. The effective therapeutic level of some drugs may also depend on the degree of plasma protein binding. Patients with alcoholic cirrhosis have reduced protein binding of dapsone,130 an agent used in dermatitis herpetiformis and leprosy, which may thus produce toxicity in therapeutic doses. This effect appears to result nonspecifically from hypoproteinemia. Drug levels of compounds rapidly metabolized by the liver may also be affected by hepatic blood flow, shown to be altered by ethanol. There has been some controversy concerning the effect of ethanol on splanchnic blood flow. Acutely, the results depend on the dose used; some investigations showed no effect131–133 or even a decrease,134 whereas most studies reported an increase.135–143 The increase in portal blood flow after ethanol administration was attributed to a preportal vasodilatory effect of adenosine formed from acetate metabolism in extrahepatic tissues.144 In general, when unchanged or decreased flow was observed, this was associated with low blood ethanol levels. Very large doses of ethanol may also produce hypothermia,145 which has been found to result in both a decrease of liver blood flow146 and a slowing of ethanol metabolism.147,148 The time of day during which experiments are carried out is also important in view of the circadian variation of ethanol metabolism,149 –151 which is particularly manifest and perhaps even altered in the alcoholic.152

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Interactions With Retinoids Effects of vitamin A deficiency Ethanol consumption has been shown to depress hepatic levels of vitamin A due, in part, to accelerated microsomal degradation.153 Indeed hepatic pathways of retinol metabolism have been discovered154,155 that are inducible by either ethanol or drug administration, and hence may contribute to the depletion. Experimentally, levels of vitamin A were depressed even in the presence of a diet containing large amounts of vitamin A.71 Depletion of vitamin A was associated with lysosomal lesions156 and decreased detoxification of nitrosodimethylamine,157 a chemical carcinogen. Concomitant ethanol consumption and vitamin A deficiency also resulted in an increased severity of squamous metaplasia of the trachea.158,159 This potentiation of vitamin A deficiency by alcohol may predispose the tracheal epithelium to neoplastic transformation. Indeed, it has been shown in animal studies that vitamin A deficiency enhances the susceptibility to neoplasm and increases carcinogenesis in the respiratory tract following the administration of carcinogenic polycyclic hydrocarbons.160,161 Conversely, treatment of animals with vitamin A or its derivatives in high doses protects against the induction of tumors in the respiratory tract.162,163 A relatively high risk of squamous cell carcinoma of the lung was found in a Norwegian population that drank large amounts of alcohol and had a low dietary intake of vitamin A.164 Furthermore, a positive association between alcohol consumption and lung cancer has been reported in Japanese men in Hawaii.165 In addition to promoting vitamin A depletion, ethanol may interfere more directly with retinoic acid synthesis as both serve as substrates for the same enzymes.166 Specifically, one of the mechanisms by which ethanol induces gastrointestinal (GI) cancer may be an inhibition of ADH-catalyzed gastrointestinal retinoic acid synthesis that is needed for epithelial differentiation. Indeed, class I ADH (ADH-I) and class IV ADH (ADH-IV) function as retinol dehydrogenases in vitro and are abundantly distributed along the GI tract.167 Furthermore, deficiency of retinoic acids can produce birth defects. Duester166,168 and Pullarkat169 incriminated competitive inhibition, by ethanol, of the biosynthesis of retinoic acid from retinol as class I alcohol dehydrogenase contributes to the biosynthesis of retinoic acid from retinol. Severe vitamin A deficiency manifests itself dermatologically by xerophthalmia, follicular hyperkeratosis (as phrynoderma, or toad skin), and generalized xerosis.170 Vitamin A excess Not only does vitamin A deficiency adversely affect the liver (vide supra), but an excess of vitamin A is also known to be hepatotoxic.171 Long-term ethanol consumption enhances this effect, resulting in striking mor-

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phologic and functional alterations of the mitochondria,172 along with hepatic necrosis and fibrosis.173 Thus, in heavy drinkers, there is a narrowed therapeutic window for vitamin A. When such patients have acne vulgaris and are treated with oral vitamin A or topical tretinoin (retin-A) (which may be systemically absorbed), they must be closely monitored for hepatotoxicity. Cutaneous manifestations of hypervitaminosis A include alopecia, dryness and fissures of the lips.170 Although vitamin A deficiency promotes carcinogenesis (vide supra), vitamin A excess may also have such an effect: Tuyns et al174 and DeCarli et al175 noted that foods providing large amounts of retinol increase the risk of cancer of the esophagus and, in an epidemiologic study, the cancer risk associated with the use of cigarettes and alcohol was also enhanced upon ingestion of foods containing retinol.176

Interactions With Carotenoids In contrast to retinoids, their natural precursors, namely carotenoids, were not known to produce toxic manifestations even when ingested chronically in large amounts.177,178 Therefore, it made sense to assess whether carotenoids may serve as effective (but less toxic) substitutes for retinol. Studies in man revealed that for a given ␤-carotene intake, a correlation exists between alcohol consumption and plasma ␤-carotene concentration.179 In general, alcoholics have low plasma ␤-carotene levels,179,180 presumably reflecting low intake. However, alcohol per se might in fact increase blood levels in man.179 There was also an increase in women, with a dose as low as two drinks a day,181 and also in nonhuman primates.182 Indeed, in baboons fed ethanol chronically, liver ␤-carotene was increased, in contrast with vitamin A, which was depleted. This was associated with a striking delay in the clearance of a load of ␤-carotene from the blood. Furthermore, whereas ␤-carotene administration increased hepatic vitamin A in control baboons, this effect was much less evident in alcohol-fed animals. The combination of an increase in ␤-carotene and a relative lack of a corresponding rise in vitamin A suggested a blockage in the conversion of ␤-carotene to vitamin A by ethanol. The relationship between liver disease and hepatic carotenoids is complex. In most patients with liver disease, absolute levels of hepatic ␣- and ␤-carotene and retinoids were found to be severely depressed, even in the presence of normal serum levels of lycopene ␣ and/or ␤-carotene; in patients with cirrhosis, hepatic levels were particularly low.183 However, even in these patients with very low liver ␣- and ␤-carotene concentrations, more than half had blood levels in the normal range, suggesting that liver disease interferes with the uptake, excretion, or perhaps the metabolism of ␣- and ␤-carotene. In only one-third of the subjects were ␣- and

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␤-carotene serum levels low, probably reflecting poor dietary intake. In baboons, the administration of ethanol, together with ␤-carotene, resulted in a more striking hepatic injury than with either compound alone.182 In the rat also, the well-known hepatotoxicity of ethanol was potentiated by large amounts of ␤-carotene, and the concomitant administration of both resulted in striking liver lesions.184 Some extrahepatic side effects were also observed. It was noted that in smokers, ␤-carotene supplementation increases death from coronary heart disease in the ATBC Study185 and in the CARET Trial.186 The toxic effects of ␤-carotene and their interaction with ethanol also involved an increased incidence of pulmonary cancer: Both the ATBC185 and the CARET186 studies revealed that ␤-carotene supplementation increases the incidence of pulmonary cancer in smokers. Because heavy smokers are commonly heavy drinkers, we raised the possibility that alcohol abuse was contributory.187 Indeed, it was shown subsequently that the increased incidence of pulmonary cancer was related to the alcohol consumed.188,189

Conclusions Alcohol has been associated with mankind ever since the dawn of civilization, yet its metabolism has only been elucidated in recent years. The main pathway proceeds via cytosolic ADH, which has multiple isoenzymes. The latest ADH isozyme to be characterized is ␴-ADH, which is prevalent in the upper GI tract and exhibits ethnic variability. Three decades ago, a new pathway of ethanol metabolism was discovered, namely the microsomal ethanol oxidizing system (MEOS), which, contrary to the ADH pathway, is highly inducible by chronic alcohol consumption. It plays a significant role in alcohol-related pathology through the increased production of the toxic metabolite acetaldehyde, the concomitant generation of free radicals, and the cross-induction of other microsomal enzymes, especially other cytochromes P450. These, in turn, activate scores of xenobiotics (including analgesics and anesthetics) to highly toxic and, at times, carcinogenic metabolites, while contributing to the degradation (and hence the depletion) of vitamin A. Because ethanol also exacerbates the toxicity of excess retinol and ␤-carotene, a narrowing of the therapeutic window for retinoids and carotenoids ensues, which impacts on the preventive and therapeutic use of those compounds in individuals who consume alcohol.

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