PMID: 8605292Dec 1, 1995Paper

Cytochrome P450 peroxidase/peroxygenase mediated xenobiotic metabolic activation and cytotoxicity in isolated hepatocytes

Chemical Research in Toxicology
M R AnariP J O'Brien

Abstract

Cytochrome P450 (P450) can utilize organic hydroperoxides and peracids to support hydroxylation and dealkylation of various P450 substrates. However, the biological significance of this P450 peroxygenase/peroxidase activity in the bioactivation of xenobiotics in intact cells has not been demonstrated. We have shown that tert-butyl hydroperoxide (tBHP) markedly enhances 3-20-fold the cytotoxicity of various aromatic hydrocarbons and their phenolic metabolites. The tBHP-enhanced hepatocyte cytotoxicity of 4-nitroanisole (4-NA) and 4-hydroxyanisole (4-HA) was also accompanied by an increase in the hepatocyte O-demethylation of 4-NA and 4-HA up to 7.5- and 21-fold, respectively. Hepatocyte GSH conjugation by 4-HA was also markedly increased by tBHP. An LC/MS analysis of the GSH conjugates identified hydroquinone-GSH and 4-methoxy-catechol:GSH conjugates as the predominant adducts. Pretreatment of hepatocytes with P450 inhibitors, e.g., phenylimidazole, prevented tBHP-enhanced 4-HA metabolism, GSH depletion, and cytotoxicity. In conclusion, hydroperoxides can therefore be used by intact cells to support the bioactivation of xenobiotics through the P450 peroxidase/peroxygenase system.

Citations

Mar 26, 1998·European Journal of Drug Metabolism and Pharmacokinetics·M R AnariP J O'Brien
Jul 16, 2008·Analytical and Bioanalytical Chemistry·Kersten S RabeChristof M Niemeyer
May 20, 1999·International Journal for Parasitology·A C Kotze
Dec 9, 2003·Amino Acids·D van der VliesJ A Post
Mar 1, 2012·Cutaneous and Ocular Toxicology·Mamta BehlRajendra S Chhabra
Nov 28, 2002·Chemico-biological Interactions·Majid Y MoridaniPeter J O'Brien
Sep 14, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·M Y MoridaniP J O'Brien
Nov 28, 2019·Environmental Science & Technology·Stefan AchermannKathrin Fenner

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