The acetaminophen regioisomer 3'-hydroxyacetanilide inhibits and covalently binds to cytochrome P450 2E1

Toxicology Letters
N C HalmesN R Pumford

Abstract

3'-Hydroxyacetanilide has been previously studied as a nontoxic regioisomer of the analgesic acetaminophen (4'-hydroxyacetanilide). The radiolabeled derivative has been shown to covalently bind to liver proteins at levels similar to that observed with hepatotoxic doses of radiolabeled acetaminophen with no evidence of hepatic damage. Using an anti-arylacetamide antiserum the primary protein adduct detected following administration of 3'-hydroxyacetanilide (300 and 600 mg/kg) to mice was a 50 kDa microsomal protein that co-migrated with cytochrome P450 2E1. Cytochrome P450 2E1 enzyme activity (p-nitrophenol hydroxylase) was decreased by 79% in the mice treated with 3'-hydroxyacetanilide (600 mg/kg). Incubation of 3'-hydroxyacetanilide with hepatic microsomes resulted in a time dependent 47% decrease in cytochrome P450 2E1 activity. Pre-incubation of acetaminophen with microsomes did not result in covalent binding to the cytochrome P450 nor was there a decrease in p-nitrophenol hydroxylase activity. These data suggest that 3'-hydroxyacetanilide covalently binds to cytochrome P450 2E1 with preferential loss of activity.

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Citations

Aug 23, 2002·Toxicology Letters·O ChikuniJ U Skaare
Jan 1, 1997·Annual Review of Pharmacology and Toxicology·N R Pumford, N C Halmes
Aug 24, 2012·Archives of Toxicology·Mackenzie HadiGeny M M Groothuis
Nov 28, 2006·Expert Opinion on Drug Metabolism & Toxicology·John Cl Erve
May 23, 2012·Drug Metabolism and Disposition : the Biological Fate of Chemicals·John P HarrelsonSidney D Nelson
Sep 14, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yasuhiro MasubuchiToshiharu Horie

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