Bernhard H. Lauterburg

N-Acetylcysteine is the drug of choice for the treatment of an acetaminophen overdose. It is thought to provide cysteine for glutathione synthesis and possibly to form an adduct directly with the toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine. However, these hypothese have not been tested in vivo, and other mechanisms of action such as reduction of the quinoneimine might be responsible for the clinical efficacy of N-acetylcysteine. After the administration to rats of acetaminophen (1 g/kg) intraduodenally (i.d.) and of [(35)S]-N-acetylcysteine (1.2 g/kg i.d.), the specific activity of the N-acetylcysteine adduct of acetaminophen (mercapturic acid) isolated from urine and assayed by high pressure liquid chromatography averaged 76+/-6% of the specific activity of the glutathione-acetaminophen adduct excreted in bile, indicating that virtually all N-acetylcysteine-acetaminophen originated from the metabolism of the glutathione-acetaminophen adduct rather than from a direct reaction with the toxic metabolite. N-Acetylcysteine promptly reversed the acetaminophen-induced depletion of glutathione by increasing glutathione synthesis from 0.54 to 2.69 mumol/g per h. Exogenous N-acetylcysteine did not increase the formation of the N-acetylcysteine and glutathione adducts of acetaminophen in fed rats. However, when rats were fasted before the administration of acetaminophen, thereby increasing the stress on the glutathione pool, exogenous N-acetylcysteine significantly increased the formation of the acetaminophen-glutathione adduct from 57 to 105 nmol/min per 100 g. Although the excretion of acetaminophen sulfate increased from 85+/-15 to 211+/-17 mumol/100 g per 24 h after N-acetylcysteine, kinetic simulations showed that increased sulfation does not significantly decrease formation of the toxic metabolite. Reduction of the benzoquinoneimine by N-acetylcysteine should result in the formation of N-acetylcysteine disulfides and glutathione disulfide via thiol-disulfide exchange. Acetaminophen alone depleted intracellular glutathione, and led to a progressive decrease in the biliary excretion of glutathione and glutathione disulfide. N-Acetylcysteine alone did not affect the biliary excretion of glutathione disulfide. However, when administered after acetaminophen. N-acetylcysteine produced a marked increase in the biliary excretion of glutathione disulfide from 1.2+/-0.3 nmol/min per 100 g in control animals to 5.7+/-0.8 nmol/min per 100 g. Animals treated with acetaminophen and N-acetylcysteine excreted 2.7+/-0.8 nmol/min per 100 g of N-acetylcysteine disulfides (measured by high performance liquid chromatography) compared to 0.4+/-0.1 nmol/min per 100 g in rats treated with N-acetylcysteine alone. In conclusion, exogenous N-acetylcysteine does not form significant amounts of conjugate with the reactive metabolite of acetaminophen in the rat in vivo but increases glutathione synthesis, thus providing more substrate for the detoxification of the reactive metabolite in the early phase of an acetaminophen intoxication when the critical reaction with vital macromolecules occurs.

Hepatic glutathione turnover and the efflux of glutathione from the liver into bile and blood were measured in male Sprague-Dawley rats in vivo. In fed rats the efflux of glutathione into blood, calculated from the hepatic arteriovenous concentration gradient and hepatic blood flow, amounted to 12.4 +/- 1.4 nmoles min X gm liver. Together with the excretion of glutathione into bile (3.4 +/- 0.4 nmoles per min X gm liver) total efflux accounted for the hepatic turnover of glutathione of 15.2 +/- 0.9 nmoles per min X gm liver. Fasting animals for 48 hr markedly increased hepatic glutathione turnover to 26.4 +/- 1.2 nmoles per min X gm liver. Increased efflux into blood rather than increased intrahepatic catabolism accounted for this increased turnover. The systemic clearance of glutathione was 3.22 +/- 0.51 ml per min X 100 gm body weight. The efflux of glutathione from liver therefore was calculated to contribute over 90% of total glutathione inflow into the circulation, as determined from the clearance and the arterial concentration of glutathione. Thus, the liver is the major source of plasma glutathione, and turnover of hepatic glutathione in the basal state is accounted for almost entirely by efflux of glutathione from the liver. During fasting, the plasma clearance of exogenous glutathione increased to 5.32 +/- 0.35 ml per min X 100 gm body weight, and the utilization of methionine for glutathione synthesis increased markedly. The increased extrahepatic catabolism during fasting results in a decrease in plasma glutathione, which in turn may account for the observed increase in sinusoidal glutathione efflux with concomitant stimulation of the rate of hepatic glutathione turnover and of synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Letters3 July 2001Kava HepatotoxicityStefan Russmann, MD, Bernhard H. Lauterburg, MD, and Arthur Helbling, MDStefan Russmann, MDUniversity of Bern; 3010 Bern, Switzerland (Russmann, Lauterburg)Inselspital; 3010 Bern, Switzerland (Helbling), Bernhard H. Lauterburg, MDUniversity of Bern; 3010 Bern, Switzerland (Russmann, Lauterburg)Inselspital; 3010 Bern, Switzerland (Helbling), and Arthur Helbling, MDUniversity of Bern; 3010 Bern, Switzerland (Russmann, Lauterburg)Inselspital; 3010 Bern, Switzerland (Helbling)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-135-1-200107030-00036 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Phytotherapeutic preparations for sleep and anxiety disorders that contain kava-lactones are available over the counter in many countries. A 33-year-old woman took the drug Laitan (Schwabe Pharma AG, Kuessnacht, Switzerland) (210 mg of kava-lactones daily) for 3 weeks. The patient reported intake of no other drugs except the homeopathic medication Exsepta (Tentan AG, Rothrist, Switzerland). Two months later, she restarted use of the kava preparation. After another 3 weeks, 1 day after intake of 60 g of alcohol, she developed malaise, loss of appetite, and jaundice. Levels of aminotransferases, bilirubin, and alkaline phosphatase were elevated 60-, 15- ...References1. Nyfeler B, Pichler WJ. The lymphocyte transformation test for the diagnosis of drug allergy: sensitivity and specificity. Clin Exp Allergy. 1997;27:175-81. [PMID: 0009061217] CrossrefMedlineGoogle Scholar2. Duffield AM, Jamieson DD, Lidgard RO, Duffield PH, Bourne DJ. Identification of some human urinary metabolites of the intoxicating beverage kava. J Chromatogr. 1989;475:273-81. [PMID: 0002777959] CrossrefMedlineGoogle Scholar3. 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[PMID: 0006479680] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: University of Bern; 3010 Bern, Switzerland (Russmann, Lauterburg)Inselspital; 3010 Bern, Switzerland (Helbling) PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoTwo Patients with Acute Liver Injury Associated with Use of the Herbal Weight-Loss Supplement Hydroxycut Tyler Stevens , Asif Qadri , and Nizar N. 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Lipid peroxidation and antioxidative mechanisms were investigated in liver mitochondria from bile duct ligated rats (BDL rats) and correlated with the activity of enzyme complexes of the electron transport chain. In comparison to pair-fed control rats, BDL rats had increased concentrations of thiobarbituric acid reacting substances (TBARS) per gram of liver and per milligram of mitochondrial protein 3, 7, 14, and 28 days after surgery. The hepatic glutathione (GSH) content was decreased in BDL rats 28 days after surgery when expressed per gram of liver but equal between BDL and control rats when expressed per liver. The mitochondrial GSH content was decreased in BDL rats by 20% to 33% from day 7 after surgery. The concentrations of ubiquinone-9 and ubiquinone-10, substances involved in electron transport and efficient antioxidants, were both decreased in BDL rats 14 and 28 days after surgery per gram of liver and per milligram of mitochondrial protein. When expressed per liver, ubiquinone-9 was decreased in BDL rats from day 7 after surgery. In comparison with controls, the decrease in total mitochondrial ubiquinone content in BDL rats averaged 52% 14 days and 38% 28 days after surgery. The activity of the succinate:ferricytochrome c oxidoreductase (complexes II and III of the electron transport chain) was decreased in BDL rats at days 7, 14, and 28 after surgery, and the activity of the ferrocytochrome c:oxygen oxidoreductase (complex IV) was reduced at 14 and 28 days after surgery. The mitochondrial concentration of TBARS showed a negative and the concentrations of GSH and ubiquinone a positive correlation with the activity of the succinate:ferricytochrome c oxidoreductase.(ABSTRACT TRUNCATED AT 250 WORDS)