Metabolic activation of o-phenylphenol to a major cytotoxic metabolite, phenylhydroquinone: role of human CYP1A2 and rat CYP2C11/CYP2E1

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
S OzawaY Ohno

Abstract

1. The in vitro metabolic activation of o-phenylphenol has been evaluated as yielding a toxic metabolite, 2,5-dihydroxybiphenyl (phenylhydroquinone), by p-hydroxylation in liver microsomes of rat and human. The involvement of rat CYP2C11, CYP2E1 and human CYP1A2 in the p-hydroxylation of o-phenylphenol is suggested. 2. 2,3- and phenylhydroquinone, which induced DNA single-strand scission in the presence of 1 microM CuCl2, were the most cytotoxic chemicals examined to cultured mammalian cell lines among o-phenylphenol, m-phenylphenol, p-phenylphenol, 2,2'-, 4,4'-, 2,3- and phenylhydroquinone. 3. Rat and human liver microsomes catalysed the formation of phenylhydroquinone, but not 2,3-dihydroxybiphenyl, using o-phenylphenol as a substrate. A higher rate of metabolic activation of o-phenylphenol was observed with livers of the male than the female rats by 5.6- and 2.6-fold respectively. 4. Inhibitory antibodies against the male-specific CYP2C11 inhibited hepatic o-phenylphenol p-hydroxylation in the male F344 and Sprague-Dawley rat by > 70%. Liver microsomes from the isoniazid-treated rats produced 1.8- and 3-fold induction of o-phenylphenol p-hydroxylation and chlorzoxazone 6-hydroxylation (a CYP2E1-dependent activity) respective...Continue Reading

References

Jan 1, 1990·Chemico-biological Interactions·F NagaiI Kano
Mar 1, 1993·Archives of Biochemistry and Biophysics·D E RyanL M Reik
Jan 1, 1995·Critical Reviews in Toxicology·A R GoeptarN P Vermeulen
Nov 5, 1999·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·M NakajimaT Yokoi
Apr 7, 2000·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·T LightfootG T Tucker

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Citations

Feb 12, 2011·Analytical and Bioanalytical Chemistry·Ruri Kikura-HanajiriYukihiro Goda
May 9, 2002·Drug Metabolism Reviews·Slobodan Rendic
Oct 24, 2009·ChemMedChem·Patrik RydbergLars Olsen
Oct 16, 2009·Journal of Applied Toxicology : JAT·Katie ChanPeter J O'Brien
Nov 3, 2004·Toxicology and Applied Pharmacology·Tracey L H JasonRandal W Berg
Dec 17, 2004·Alternatives to Laboratory Animals : ATLA·Robert D Combes
Sep 30, 2020·Toxicological Sciences : an Official Journal of the Society of Toxicology·Chad DeisenrothRussell S Thomas

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