Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity.
Patients chronically abusing ethanol are more susceptible to the hepatotoxic effects of paracetamol. This could be due to an increased activation of the drug to a toxic metabolite or to a decreased capacity to detoxify the toxic metabolite by conjugation with glutathione (GSH). To test these hypotheses paracetamol 2 g was administered to five chronic alcoholics without clinical evidence of alcoholic liver disease and five control subjects. The urinary excretion of cysteine- plus N-acetyl-cysteine-paracetamol, the two major products of detoxification of the reactive metabolite of paracetamol, was not significantly higher in chronic alcoholics arguing against a substantially increased metabolic activation of paracetamol. Chronic alcoholics had significantly lower plasma concentrations of GSH than healthy volunteers, however (4.35 (1.89) microM v 8.48 (2.68) microM, p less than 0.05) before the administration of paracetamol, and plasma GSH reached lower concentrations in the alcoholics after paracetamol (2.40 (1.36) v 6.26 (2.96) microM). In a group of patients with alcoholic hepatitis intrahepatic GSH was significantly lower than in patients with chronic persistent hepatitis and patients with non-alcoholic cirrhosis, suggesting that low plasma GSH in alcoholics reflects low hepatic concentrations of GSH. The data indicate that low GSH may be a risk factor for paracetamol hepatotoxicity in alcoholics because a lower dose of paracetamol will be necessary to deplete GSH below the critical threshold concentration where hepatocellular necrosis starts to occur.
Lauterburg
B H
BH
Department of Clinical Pharmacology, University of Berne, Switzerland.
Velez
M E
ME
D000082:Acetaminophen / Q000009:adverse effects* / Q000378:metabolism; D000437:Alcoholism / Q000150:complications* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D003545:Cysteine / Q000652:urine; D005978:Glutathione / Q000097:blood / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D012307:Risk Factors
D000082:Acetaminophen; D005978:Glutathione; D003545:Cysteine