Resistance of some phase II biotransformation pathways to hepatotoxins

Z. Gregus, J. B. Watkins, T. N. Thompson, C. D. Klaassen

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42 Scopus citations

Abstract

Effect of acute exposure of rats to allyl alcohol (0.05 ml/kg i.p.), aflatoxin B1 (5 mg/kg i.p.), carbon tetrachloride (1.0 ml/kg i.p.), 1,1-dichloroethylene (500 mg/kg p.o.), bromobenzene (0.8 ml/kg i.p.), cadmium chloride (3.9 mg/kg i.v.) and α-naphthylisothiocyanate (200 mg/kg p.o.) on the activity of enzymes of hepatic phase I (cytochrome P-450-linked microsomal monooxygenases, epoxide hydrolase) and phase II (glucuronyl-, glutathione-, acetyl- and sulfotransferases) biotransformation has been studied in rats. Hepatotoxins reduced hepatic cytochrome P-450 in liver (14-62%) and the activities of ethylmorphine demethylase (21-92%) and the activities of ethylmorphine demethylase (21-92%), benzphetamine demethylase (32-89%), benzo(a)pyrene hydroxylase (63-95%) and ethoxyresorufin deethylase (16-84%). Centrilobular liver necrosis induced by carbon tetrachloride and 1,1-dichloroethylene diminished cytochrome P-450 concentration and microsomal mixed-function oxidase activities considerably more than periportal injury produced by allyl alcohol and aflatoxin B1. This is in agreement with the uneven distribution of microsomal monooxygenases in the hepatic lobule. In contrast to that observed with P-450 mixed-function oxidases, no significant decreases in epoxide hydrolase or glucuronyltransferase activities were observed after hepatotoxin poisoning. The activities of cytosolic conjugating enzymes (glutathione-, sulfo- and acetyltransferases) also were minimally affected by toxic liver injury. Bromobenzene produced a complex effect by decreasing cytochrome P-450 concentration and cytochrome P-450-linked oxidase activities and increasing epoxide hydrolase, glucuronyl- and glutathione transferases. Inasmuch as marked differences in activity of epoxide hydrolase and glucuronyl-, glutathione-, acetyl- and sulfotransferases were not observed after chemically induced necrosis of specific regions of the hepatic lobule, reliable information on intralobular localization of these enzymes cannot be obtained by this experimental technique.

Original languageEnglish (US)
Pages (from-to)471-479
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume222
Issue number2
StatePublished - 1982

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Gregus, Z., Watkins, J. B., Thompson, T. N., & Klaassen, C. D. (1982). Resistance of some phase II biotransformation pathways to hepatotoxins. Journal of Pharmacology and Experimental Therapeutics, 222(2), 471-479.