| Abstract
| - We show that the naturally occurring hydroperoxide hydrogenperoxide is highly effectivein supporting the cytochrome P450 1A2 peroxygenase-catalyzed metabolicactivation of theheterocyclic aromatic amine2-amino-3-methylimidazo[4,5-f]quinoline (IQ) togenotoxic metabolites. Mutagenicity was assessed by the Ames assay withSalmonellatyphimurium strainYG1012 and an activation system consisting of hydroperoxides pluseither 3-methylcholanthrene-induced rat liver microsomes (rP4501A) or human P4501A2-containing microsomes(hP4501A2). The mutagenic response was dependent on theconcentration of microsomalprotein, IQ, and hydroperoxides. The addition of hydrogen peroxideor tert-butyl hydroperoxideto rP4501A greatly enhanced the yield of histidine prototrophic(His+) revertants. This increasewas inhibited, in a concentration-dependent manner, byα-naphthoflavone, a P450 1A inhibitor.Hydrogen peroxide was the most effective peroxygenase cofactor,particularly with hP4501A2(Km = 0.1 mM). Thehydroperoxide-supported activation of IQ produced reactiveintermediateswhich bound to 2‘-deoxyguanosine; LC/MS analysis of the adductsrevealed the same major(protonated) adduct at m/z = 464.4 as previously reportedfor the DNA adduct formed (invivo or invitro) by the mixedfunction-catalyzed bioactivation system. None of theperoxidase-catalyzed IQ metabolites (nitro-, azo-, or azoxy-IQ) were detected.In conclusion, hydrogenperoxide in the physiological/pathological concentration range may beable to support themetabolic activation of arylamines to genotoxic products through thecytochrome P450peroxygenase pathway.
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