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Cysteine, N-Acetyl-l
Cysteine, N-Acetyl-L SR Clough, Bedford, NH, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the original print edition article by David M Krentz and Linda A Malley, volume 1, pp 392–393, Ó 1998, Elsevier Inc.
l
Chemical Abstracts Service Registry Number: 616-91-1 Synonyms: L-a-Acetamido-b-mercaptopropionic acid, Acetylcysteine, Airbron, Broncholysin, Brunac, Fabrol, Fluatox, Fluimucetin, Fluimucil, Fluprowit, Inspir, L-a-Acetamidob-mercaptopropionic acid, Mercapturic acid, Mucocedyl; Mucolator, Mucolyticum, Mucomyst, Muco Sanigen, Mucosil, Mucosol, Mucosolvin, Mucret, N-Acetyl-L-cysteine (NAC), N-Acetyl-L-(b)-cysteine, N-Acetyl-3-mercaptoalanine (IUPAC), Neo-Fluimucil, Parvolex, Respaire, Tixair l Chemical/Pharmaceutical/Other Class: Mucolytic, Antidote l Chemical Formula: C5H9NO3S l Chemical Structure: l
as paraquat, urethane, aflatoxin, Escherichia coli, carbon tetrachloride, chloroform, and carbon monoxide. NAC is also used for preventing alcoholic liver damage, for reducing toxicity of ifosfamide and doxorubicin (drugs that are used for cancer treatment), as a hangover remedy, for preventing kidney damage due to certain X-ray dyes, and for human immunodeficiency virus.
Exposure Routes and Pathways The most common route of exposure to NAC is (voluntary) inhalation via the respiratory tract. Inhalation of 1–2 mL of a 10% solution may be given as often as every hour. Although not approved by the US Food and Drug Administration, it may be given intravenously in emergency situations. According to a National Institute for Occupational Safety and Health survey conducted between 1981 and 1983, over 30,000 workers in the United States are exposed to NAC on a daily basis. Over twothirds of those people are inhalation therapists and clinical laboratory technicians, with the remaining majority in some type of medical profession.
Toxicokinetics
Uses N-Acetyl-L-cysteine (NAC) is a white crystalline powder that melts in the range of 104–110 C and has a very slight odor. It is a natural sulfur-containing compound that is produced in living organisms from the amino acid cysteine. It is involved in the intracellular synthesis of a chemical called glutathione (GSH). Cells (particularly liver cells) use GSH to detoxify chemicals by making them more water soluble and thus easier to excrete from the body. NAC is also a powerful antioxidant. NAC is primarily marketed and used as a mucolytic agent to break up mucus (by reducing disulfide bonds in mucoproteins) in persons having bronchopulmonary diseases including chronic bronchitis, cystic fibrosis, asthma, sinusitis, and pneumonia. It is also used extensively as an antidote for acetaminophen (paracetamol) overdose or toxicity. Because it is a precursor of GSH, it has been proven useful in replenishing depleted GSH levels in the liver. Other studies have shown it can be used as a chelating agent for the treatment of heavy metal (mercury, lead, cadmium) poisoning. Other reports (primarily animal studies) have suggested that NAC can find use as a detoxifying agent for a number of toxicants, such
1122
Oral administration of NAC has poor bioavailability, ranging from 4 to 10%. Following oral administration, peak plasma levels occur within 2 or 3 h. With intravenous administration, peak plasma levels occur immediately. Orally administered NAC appears to distribute primarily to the kidneys, liver, and lungs. It is detectable in pulmonary secretions for at least 5 h after the dose. Following respiratory exposure, NAC is rapidly absorbed and exists as the free species in plasma with a concomitant increase both in plasma L-acetylcysteine levels and in protein and nonprotein sulfhydryl concentrations. Protein binding is approximately 83%. The volume of distribution in humans is 0.337–0.47 l kg 1. Thirty percent of intravenously administered NAC is renally cleared. NAC elimination is not impaired in patients with severe liver damage. The terminal half-life of NAC is 2–6 h and is increased to 11 h in newborns. This may be increased to 13 h after an intravenous injection.
Mechanism of Toxicity Fatalities from normal doses and overdoses of intravenous NAC have not been reported. This is most probably due to the fact that the body produces this compound naturally and can rapidly metabolize it in the liver. Toxicity is usually limited to anaphylactoid reactions and nausea/vomiting. The average time for the onset of adverse effects following commencement
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00485-1
Cysteine, N-Acetyl-L
1123
of the infusion of NAC was 30 min (range, 5–70 min). In vivo and in vitro tests indicate that NAC is an inhibitor of allergen tolerance by inhibition of prostaglandin E synthesis. Adverse reactions are anaphylactoid in type and have been attributed to cause histamine release.
damage probably far outweighs any potential risk of N-acetylcysteine, and pregnancy should not be considered a contraindication to the use of this agent.
Acute and Short-Term Toxicity (or Exposure)
N-Acetylcysteine is negative in the Ames mutagenicity test and also reduces the mutagenic effect of chemical carcinogens in the same assay.
N-Acetylcysteine is used primarily in the treatment of acetaminophen (paracetamol) overdose and/or toxicity. It is also nebulized for mucolytic effects and less often used to treat corneal ulcers. It has a very low potential to cause acute toxicity in either animals or humans.
Animal Oral formulations of N-acetylcysteine are used intravenously in the clinical treatment of animals, although it has not been approved for this use. The Registry of Toxic Effects of Chemical Substances (RTECS) lists an acute oral, intravenous, and intraperitoneal LD50 in dogs of 1.0, 0.7, and 0.7 g kg 1 body weight, respectively. For mice, RTECS lists an oral, intravenous, and intraperitoneal LD50 of 4.4, 3.8, and 0.4 g kg 1 body weight, respectively. For rats, RTECS lists an oral and intravenous LD50 of 5.05 and 1.14 g kg 1 body weight, respectively. Acute effects cited for mice include central nervous system depression and somnolence; rats showed gastrointestinal changes.
Human The primary toxicity of NAC consists of nausea/vomiting, particularly after oral therapy, and an anaphylactoid reaction, particularly after IV administration, that may be life threatening. Many cases of anaphylactic reactions have been reported with symptoms primarily consisting of rash, nausea, hypotension, bronchospasm, angioedema, tachycardia, and respiratory distress. NAC may also have some neurological toxicity that includes dizziness, intracranial hypertension, hypoactivity, ataxia, and seizures. There have been reports of mucosal damage with full strength (20%) NAC, which causes hyperemia and hemorrhages of bowel mucosa. During inhalation therapy, irritation or soreness of the mouth may occur. The RTECS cites a ‘lowest published toxic dose’ reported for a child of 8.48 g kg 1 over a 3-day period. This is a relatively large dose and places this substance in the acute category of ‘practically nontoxic.’
Chronic Toxicity (or Exposure) Animal
In Vitro Toxicity Data
Clinical Management Since 1974, it has been known, and generally accepted, that NAC is hepatoprotective, especially for treating overdoses of acetaminophen. Basic and advanced life-support measures should be utilized as necessary. For acetaminophen overdose, a 140 mg kg 1 dose followed by 70 mg kg 1 every 4 h for an additional 17 doses should be administered. Since NAC has not been approved for intravenous administration, assistance is available through the Rocky Mountain Poison Center. NAC should not be mixed with erythromycin lactobionate or tetracycline.
Environmental Fate Because NAC is a natural compound that contains no halogen atoms or substitutions, it would be expected to be easily metabolized by microorganisms in the environment and thus not present a risk from the standpoint of persistence or bioaccumulation.
Ecotoxicology NAC is produced naturally in the body and is therefore not anticipated to be a hazard to ecological receptors.
Exposure Standards and Guidelines There are no regulatory exposure standards or guidelines for NAC. Acute doses of 140 mg kg 1 are recommended for the initial ‘loading’ dose in humans (i.e., for paracetamol poisoning) and 1330 mg kg 1 can be tolerated by humans over a 72-h period.
See also: Acetaminophen; Aflatoxin; Alcoholic Beverages and Health Effects; Carbon Tetrachloride; Chloroform; Carbon Monoxide; Escherichia coli (Escherichia Coli); Ethanol; Glutathione; Paraquat; Nitrite Inhalants.
NAC has not been shown to cause birth defects in rats or rabbits. When administered to rabbits during the critical phase of embryogenesis, no malformation resulted.
Further Reading Human Experience in 59 pregnant patients suggested that use of NAC in pregnancy did not result in toxic effects on the fetus. In practice, the risk to the mother and baby of paracetamol-induced liver
Meredith, T.J., Jacobsen, T., Haines, J.A., Berger, J.C., (Eds.), 1995. IPCS/CES Evaluation of Antidotes Series. Antidotes for Poisoning by Paracetamol, vol. 3 Cambridge University Press on behalf of the World Health Organization and of the Commission of the European Communities.
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Cysteine, N-Acetyl-L
Relevant Websites http://www.drugs.com/ppa/acetylcysteine-n-acetylcysteine.html – Drugs.com (Drug Information Online) http://www.intox.org – IPCS INTOX Data Bank.
http://www.rxlist.com – The Internet Drug Index. http://chem.sis.nlm.nih.gov/chemidplus/ – US National Library of Medicine http://www.fda.gov – US Food and Drug Administration. http://www.webmd.com – WebMD.
l
Chemical Abstracts Service Registry Number: 616-91-1 Synonyms: L-a-Acetamido-b-mercaptopropionic acid, Acetylcysteine, Airbron, Broncholysin, Brunac, Fabrol, Fluatox, Fluimucetin, Fluimucil, Fluprowit, Inspir, L-a-Acetamidob-mercaptopropionic acid, Mercapturic acid, Mucocedyl; Mucolator, Mucolyticum, Mucomyst, Muco Sanigen, Mucosil, Mucosol, Mucosolvin, Mucret, N-Acetyl-L-cysteine (NAC), N-Acetyl-L-(b)-cysteine, N-Acetyl-3-mercaptoalanine (IUPAC), Neo-Fluimucil, Parvolex, Respaire, Tixair l Chemical/Pharmaceutical/Other Class: Mucolytic, Antidote l Chemical Formula: C5H9NO3S l Chemical Structure: l
as paraquat, urethane, aflatoxin, Escherichia coli, carbon tetrachloride, chloroform, and carbon monoxide. NAC is also used for preventing alcoholic liver damage, for reducing toxicity of ifosfamide and doxorubicin (drugs that are used for cancer treatment), as a hangover remedy, for preventing kidney damage due to certain X-ray dyes, and for human immunodeficiency virus.
Exposure Routes and Pathways The most common route of exposure to NAC is (voluntary) inhalation via the respiratory tract. Inhalation of 1–2 mL of a 10% solution may be given as often as every hour. Although not approved by the US Food and Drug Administration, it may be given intravenously in emergency situations. According to a National Institute for Occupational Safety and Health survey conducted between 1981 and 1983, over 30,000 workers in the United States are exposed to NAC on a daily basis. Over twothirds of those people are inhalation therapists and clinical laboratory technicians, with the remaining majority in some type of medical profession.
Toxicokinetics
Uses N-Acetyl-L-cysteine (NAC) is a white crystalline powder that melts in the range of 104–110 C and has a very slight odor. It is a natural sulfur-containing compound that is produced in living organisms from the amino acid cysteine. It is involved in the intracellular synthesis of a chemical called glutathione (GSH). Cells (particularly liver cells) use GSH to detoxify chemicals by making them more water soluble and thus easier to excrete from the body. NAC is also a powerful antioxidant. NAC is primarily marketed and used as a mucolytic agent to break up mucus (by reducing disulfide bonds in mucoproteins) in persons having bronchopulmonary diseases including chronic bronchitis, cystic fibrosis, asthma, sinusitis, and pneumonia. It is also used extensively as an antidote for acetaminophen (paracetamol) overdose or toxicity. Because it is a precursor of GSH, it has been proven useful in replenishing depleted GSH levels in the liver. Other studies have shown it can be used as a chelating agent for the treatment of heavy metal (mercury, lead, cadmium) poisoning. Other reports (primarily animal studies) have suggested that NAC can find use as a detoxifying agent for a number of toxicants, such
1122
Oral administration of NAC has poor bioavailability, ranging from 4 to 10%. Following oral administration, peak plasma levels occur within 2 or 3 h. With intravenous administration, peak plasma levels occur immediately. Orally administered NAC appears to distribute primarily to the kidneys, liver, and lungs. It is detectable in pulmonary secretions for at least 5 h after the dose. Following respiratory exposure, NAC is rapidly absorbed and exists as the free species in plasma with a concomitant increase both in plasma L-acetylcysteine levels and in protein and nonprotein sulfhydryl concentrations. Protein binding is approximately 83%. The volume of distribution in humans is 0.337–0.47 l kg 1. Thirty percent of intravenously administered NAC is renally cleared. NAC elimination is not impaired in patients with severe liver damage. The terminal half-life of NAC is 2–6 h and is increased to 11 h in newborns. This may be increased to 13 h after an intravenous injection.
Mechanism of Toxicity Fatalities from normal doses and overdoses of intravenous NAC have not been reported. This is most probably due to the fact that the body produces this compound naturally and can rapidly metabolize it in the liver. Toxicity is usually limited to anaphylactoid reactions and nausea/vomiting. The average time for the onset of adverse effects following commencement
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00485-1
Cysteine, N-Acetyl-L
1123
of the infusion of NAC was 30 min (range, 5–70 min). In vivo and in vitro tests indicate that NAC is an inhibitor of allergen tolerance by inhibition of prostaglandin E synthesis. Adverse reactions are anaphylactoid in type and have been attributed to cause histamine release.
damage probably far outweighs any potential risk of N-acetylcysteine, and pregnancy should not be considered a contraindication to the use of this agent.
Acute and Short-Term Toxicity (or Exposure)
N-Acetylcysteine is negative in the Ames mutagenicity test and also reduces the mutagenic effect of chemical carcinogens in the same assay.
N-Acetylcysteine is used primarily in the treatment of acetaminophen (paracetamol) overdose and/or toxicity. It is also nebulized for mucolytic effects and less often used to treat corneal ulcers. It has a very low potential to cause acute toxicity in either animals or humans.
Animal Oral formulations of N-acetylcysteine are used intravenously in the clinical treatment of animals, although it has not been approved for this use. The Registry of Toxic Effects of Chemical Substances (RTECS) lists an acute oral, intravenous, and intraperitoneal LD50 in dogs of 1.0, 0.7, and 0.7 g kg 1 body weight, respectively. For mice, RTECS lists an oral, intravenous, and intraperitoneal LD50 of 4.4, 3.8, and 0.4 g kg 1 body weight, respectively. For rats, RTECS lists an oral and intravenous LD50 of 5.05 and 1.14 g kg 1 body weight, respectively. Acute effects cited for mice include central nervous system depression and somnolence; rats showed gastrointestinal changes.
Human The primary toxicity of NAC consists of nausea/vomiting, particularly after oral therapy, and an anaphylactoid reaction, particularly after IV administration, that may be life threatening. Many cases of anaphylactic reactions have been reported with symptoms primarily consisting of rash, nausea, hypotension, bronchospasm, angioedema, tachycardia, and respiratory distress. NAC may also have some neurological toxicity that includes dizziness, intracranial hypertension, hypoactivity, ataxia, and seizures. There have been reports of mucosal damage with full strength (20%) NAC, which causes hyperemia and hemorrhages of bowel mucosa. During inhalation therapy, irritation or soreness of the mouth may occur. The RTECS cites a ‘lowest published toxic dose’ reported for a child of 8.48 g kg 1 over a 3-day period. This is a relatively large dose and places this substance in the acute category of ‘practically nontoxic.’
Chronic Toxicity (or Exposure) Animal
In Vitro Toxicity Data
Clinical Management Since 1974, it has been known, and generally accepted, that NAC is hepatoprotective, especially for treating overdoses of acetaminophen. Basic and advanced life-support measures should be utilized as necessary. For acetaminophen overdose, a 140 mg kg 1 dose followed by 70 mg kg 1 every 4 h for an additional 17 doses should be administered. Since NAC has not been approved for intravenous administration, assistance is available through the Rocky Mountain Poison Center. NAC should not be mixed with erythromycin lactobionate or tetracycline.
Environmental Fate Because NAC is a natural compound that contains no halogen atoms or substitutions, it would be expected to be easily metabolized by microorganisms in the environment and thus not present a risk from the standpoint of persistence or bioaccumulation.
Ecotoxicology NAC is produced naturally in the body and is therefore not anticipated to be a hazard to ecological receptors.
Exposure Standards and Guidelines There are no regulatory exposure standards or guidelines for NAC. Acute doses of 140 mg kg 1 are recommended for the initial ‘loading’ dose in humans (i.e., for paracetamol poisoning) and 1330 mg kg 1 can be tolerated by humans over a 72-h period.
See also: Acetaminophen; Aflatoxin; Alcoholic Beverages and Health Effects; Carbon Tetrachloride; Chloroform; Carbon Monoxide; Escherichia coli (Escherichia Coli); Ethanol; Glutathione; Paraquat; Nitrite Inhalants.
NAC has not been shown to cause birth defects in rats or rabbits. When administered to rabbits during the critical phase of embryogenesis, no malformation resulted.
Further Reading Human Experience in 59 pregnant patients suggested that use of NAC in pregnancy did not result in toxic effects on the fetus. In practice, the risk to the mother and baby of paracetamol-induced liver
Meredith, T.J., Jacobsen, T., Haines, J.A., Berger, J.C., (Eds.), 1995. IPCS/CES Evaluation of Antidotes Series. Antidotes for Poisoning by Paracetamol, vol. 3 Cambridge University Press on behalf of the World Health Organization and of the Commission of the European Communities.
1124
Cysteine, N-Acetyl-L
Relevant Websites http://www.drugs.com/ppa/acetylcysteine-n-acetylcysteine.html – Drugs.com (Drug Information Online) http://www.intox.org – IPCS INTOX Data Bank.
http://www.rxlist.com – The Internet Drug Index. http://chem.sis.nlm.nih.gov/chemidplus/ – US National Library of Medicine http://www.fda.gov – US Food and Drug Administration. http://www.webmd.com – WebMD.