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Selective Inhibition of Acetaminophen Oxidation and Toxicity by Cimetidine and Other Histamine H2-Receptor Antagonists in Vivo and in Vitro in the Rat and in Man

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Selective Inhibition of Acetaminophen Oxidation and Toxicity by Cimetidine and Other Histamine H2-Receptor Antagonists in Vivo and in Vitro in the Rat and in Man Selective inhibition of acetaminophen oxidation and toxicity by cimetidine and other histamine H2-receptor antagonists in vivo and in vitro in the rat and in man. M C Mitchell, … , S Schenker, K V Speeg Jr J Clin Invest. 1984;73(2):383-391. https://doi.org/10.1172/JCI111223. Research Article Acetaminophen-induced hepatotoxicity results from hepatic enzymatic oxidation of acetaminophen to a toxic, electrophilic intermediate. Acetaminophen is ordinarily eliminated after conjugation with glucuronic acid and sulfate to nontoxic derivatives. Cimetidine has been shown to inhibit the hepatic oxidation of a number of drugs and to protect rats from acetaminophen-induced hepatic necrosis. The aim of this study was to define the mechanism by which cimetidine reduced acetaminophen-induced hepatic necrosis and to determine whether inhibition of formation of the reactive metabolite(s) of acetaminophen occurred also in man. In vivo cimetidine pretreatment decreased covalent binding of [3H]acetaminophen to the liver from 552 +/- 23.8 to 170 +/- 31.6 nmol/g protein 2 h after a toxic dose of acetaminophen in 3-methylcholanthrene pretreated rats (P less than 0.05). Cimetidine pretreatment also significantly reduced the rate of hepatic glutathione depletion. Both cimetidine and metiamide produced dose-dependent inhibition of acetaminophen oxidation in vitro, whereas inhibition by ranitidine and cimetidine sulfoxide was quantitatively less. Inhibition of acetaminophen oxidation by cimetidine and metiamide was primarily competitive with an inhibition constant (Ki) of 130 +/- 16 and 200 +/- 50 microM, respectively. By contrast, cimetidine inhibited acetaminophen glucuronidation minimally with a Ki of 1.39 +/- 0.23 mM. Similar results were obtained using human liver microsomes as a source of enzymes. In a dose- related fashion, cimetidine also reduced acetaminophen-induced toxicity to human […] Find the latest version: https://jci.me/111223/pdf Selective Inhibition of Acetaminophen Oxidation and Toxicity by Cimetidine and Other Histamine H2-Receptor Antagonists In Vivo and In Vitro in the Rat and in Man Mack C. Mitchell, Steven Schenker, and K. V. Speeg, Jr. Department ofMedicine, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205; Department of Medicine, University of Texas Health Science Center and Audie Murphy Veterans Administration Medical Center, San Antonio, Texas 78284 Abstract. Acetaminophen-induced hepatotox- with an inhibition constant (Ki) of 130±16 and 200±50 icity results from hepatic enzymatic oxidation of acet- MM, respectively. By contrast, cimetidine inhibited acet- aminophen to a toxic, electrophilic intermediate. Acet- aminophen glucuronidation minimally with a Ki of aminophen is ordinarily eliminated after conjugation with 1.39±0.23 mM. Similar results were obtained using hu- glucuronic acid and sulfate to nontoxic derivatives. Ci- man liver microsomes as a source of enzymes. In a dose- metidine has been shown to inhibit the hepatic oxidation related fashion, cimetidine also reduced acetaminophen- of a number of drugs and to protect rats from acetamin- induced toxicity to human lymphocytes when incubated ophen-induced hepatic necrosis. The aim of this study with microsomes and NADPH. Pharmacokinetics of was to define the mechanism by which cimetidine reduced acetaminophen elimination were studied in normal vol- acetaminophen-induced hepatic necrosis and to deter- unteers with and without co-administration ofcimetidine mine whether inhibition of formation of the reactive me- 300 mg every 6 h. In normal volunteers, cimetidine de- tabolite(s) of acetaminophen occurred also in man. In creased the fractional clearance ofthe oxidized (potentially vivo cimetidine pretreatment decreased covalent binding toxic) metabolites of acetaminophen more than the con- of [3H]acetaminophen to the liver from 552±23.8 to jugated metabolites. This finding confirmed the hypothesis 170±31.6 nmol/g protein 2 h after a toxic dose of acet- that cimetidine is a relatively selective inhibitor of the aminophen in 3-methylcholanthrene pretreated rats (P oxidation of acetaminophen to reactive metabolites in < 0.05). Cimetidine pretreatment also significantly re- man as well as in animals. When considered together duced the rate of hepatic glutathione depletion. Both ci- with the results of previous studies showing improved metidine and metiamide produced dose-dependent in- survival and decreased hepatotoxicity in acetaminophen- hibition of acetaminophen oxidation in vitro, whereas poisoned animals, the present results provide a rational inhibition by ranitidine and cimetidine sulfoxide was basis for assessing possible benefits ofcimetidine treatment quantitatively less. Inhibition of acetaminophen oxidation of acetaminophen overdoses in man. by cimetidine and metiamide was primarily competitive Introduction Portions of this study were published in abstract form. 1981. Clin. Res. Acetaminophen is a commonly used analgesic that has been 29:758A; 1982. Hepatology. 2:731A. shown to cause dose-related hepatic necrosis in both laboratory Address all correspondence to Dr. K. V. Speeg, Jr., Department of animals and in humans after massive doses (1, 2). This dose- Medicine, University of Texas Health Science Center, San Antonio, TX related hepatotoxicity is believed to result from metabolic con- 78284. version of acetaminophen to a highly reactive, electrophilic in- Dr. Mitchell was the recipient of a National Research Service Fel- termediate by the cytochrome P-450 mixed function oxidase lowship, AM 06566-01 and a Research Fellowship Award from the complex (1). Once formed this toxic intermediate may alkylate American Liver Foundation. tissue macromolecules unless detoxified by further conjugation 28 1982 and in 29 Receivedfor publication April revisedform Sep- oxidation is a tember 1983. with glutathione. Cytochrome P450-mediated minor pathway in the overall biotransformation and elimination J. Clin Invest. of acetaminophen. After usual therapeutic doses only a small © The American Society for Clinical Investigations, Inc. amount ofthis toxic intermediate is formed. The major pathways 0021-9738/84/02/383/09 in acetaminophen biotransformation are the phase II conjugation Volume 73, February 1984, 383-391 reactions: glucuronidation and sulfation (3). These latter two 383 Inhibition ofAcetaminophen Oxidation by Cimetidine pathways account for - 80-90% of the metabolism of acet- was purchased from New England Nuclear (Boston, MA). Synthetic aminophen, except after large doses, when sulfation may become standards of acetaminophen-cysteine, acetaminophen, and acetamin- saturated (4). The oxidized metabolites of acetaminophen are ophen glucuronide were donated by Dr. Josiah Tam of McNeil Lab- excreted in urine as mercapturic acid and cysteine conjugates, oratories (Fort Washington, PA). All other reagents were of the highest grade commercially available. which represent degradation products of the acetaminophen- and de- glutathione adduct. At low doses of acetaminophen these com- In vivo covalent binding of[3H]acetaminophen glutathione pletion. Animals were pretreated with 3-MC 72 h before receiving 500 pounds serve as an index of the potentially toxic oxidation of mg/kg of acetaminophen and 200 ,Ci/kg of [3H]acetaminophen in saline acetaminophen while the glucuronide and sulfate conjugates as a single intraperitoneal injection. There were three animals in each represent nontoxic elimination. Current therapy of acetamin- group at each time point. Halfofthe rats received 150 mg/kg of cimetidine ophen overdoses includes administration of N-acetylcysteine, and the other half received an equal volume of saline (0.1 ml i.p.) 30 which protects against necrosis by increasing synthesis of glu- min before the acetaminophen dose. Rats were killed at 30, 60, 90, and tathione, providing active sulfate, and/or by reduction of the 120 min after receiving acetaminophen. The livers were removed, blotted electrophilic intermediate (N-acetyl-p-benzoquinoneimine) back dry with filter paper, weighed, and homogenized in 20 ml of 10% tri- to the parent compound (5). chloroacetic acid (TCA) in 0.01 N HCI. The precipitate was washed Cimetidine, a 4-5 substituted imidazole used widely as a extensively with methanol until radioactivity in the supernatant was decreased to levels. was solubilized with has been demonstrated to background Precipitated protein histamine H2-receptor antagonist, 2.0 N NaOH overnight and aliquots were removed for counting by cause dose-related inhibition of cytochrome P-450-mediated liquid scintillation spectrometry or for determination of protein using oxidation both in vivo and in vitro (6-8). This inhibition of the method of Lowry et al. (13). Results were expressed as nanomoles cytochrome P-450-mediated drug metabolism by cimetidine acetaminophen covalently bound per gram of liver protein after solu- seems to be related to its imidazole structure rather than to its bilization. H2-receptor antagonist potency. Ranitidine, a substituted furan, Total hepatic glutathione levels in the initial supernatant after ho- exhibits higher H2-receptor antagonist potency, but is far less mogenization of the liver were measured using the method of Tietze active than cimetidine in inhibiting drug oxidation (6-8). Fur- (14). Results were expressed as micrograms of glutathione per gram thermore, this inhibition of oxidative drug metabolism appears liver (wet weight). of has been Enzyme assays. Hepatic microsomes were prepared from 3-MC- to be relatively selective, as glucuronidation
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