Hydrogen peroxide supports human and rat cytochrome P450 1A2-catalyzed 2-amino-3-methylimidazo[4,5-f]quinoline bioactivation to mutagenic metabolites: significance of cytochrome P450 peroxygenase

Chemical Research in Toxicology
M R AnariP J O'Brien

Abstract

We show that the naturally occurring hydroperoxide hydrogen peroxide is highly effective in supporting the cytochrome P450 1A2 peroxygenase-catalyzed metabolic activation of the heterocyclic aromatic amine 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to genotoxic metabolites. Mutagenicity was assessed by the Ames assay with Salmonella typhimurium strain YG1012 and an activation system consisting of hydroperoxides plus either 3-methylcholanthrene-induced rat liver microsomes (rP4501A) or human P450 1A2-containing microsomes (hP4501A2). The mutagenic response was dependent on the concentration of microsomal protein, IQ, and hydroperoxides. The addition of hydrogen peroxide or tert-butyl hydroperoxide to rP4501A greatly enhanced the yield of histidine prototrophic (His+) revertants. This increase was inhibited, in a concentration-dependent manner, by alpha-naphthoflavone, a P450 1A inhibitor. Hydrogen peroxide was the most effective peroxygenase cofactor, particularly with hP4501A2 (K(m) = 0.1 mM). The hydroperoxide-supported activation of IQ produced reactive intermediates which bound to 2'-deoxyguanosine; LC/MS analysis of the adducts revealed the same major (protonated) adduct at m/z = 464.4 as previously reported for the DNA a...Continue Reading

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Citations

Sep 25, 2003·European Journal of Drug Metabolism and Pharmacokinetics·I AndreadouP N Kourounakis
Mar 26, 1998·European Journal of Drug Metabolism and Pharmacokinetics·M R AnariP J O'Brien
May 1, 2012·Applied Biochemistry and Biotechnology·Atul ShrivastavaGitika Bhatia
Jul 18, 2002·Toxicology Letters·Majid Y MoridaniPeter J O'Brien
Aug 24, 2012·Mutagenesis·Maria TsamouJoost H M van Delft
Mar 21, 2007·Chemistry & Biodiversity·Bernard Testa, Stefanie D Krämer
May 17, 2005·Drug Discovery Today·Shahrzad Tafazoli, Peter J O'Brien
Dec 7, 2002·Nutrition and Cancer·Beverly A MontgomeryAnane Aidoo
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Feb 7, 2014·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Osami Shoji, Yoshihito Watanabe
Apr 3, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Silja J StrohmaierElizabeth M J Gillam
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Sep 17, 2021·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·Takehiko Nohmi, Masahiko Watanabe

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