human liver microsomes containing P₄₅₀₁A₂

• 英文名称: human liver microsomes containing P₄₅₀₁A₂

反应信息

• 作为试剂：
  描述：

  甲氧基异酚恶唑 在 human liver microsomes containing P₄₅₀₁A₂ 双氧水 作用下， 以 phosphate buffer 、 二甲基亚砜 为溶剂， 反应 0.05h， 生成 试卤灵
  参考文献：
  名称：

  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

  摘要：

  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 P4501A 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 mit = 464.4 as previously reported for the DNA adduct formed (in vivo or in vitro) by the mixed function-catalyzed bioactivation system. None of the peroxidase-catalyzed IQ metabolites (nitro-, azo-, or azoxy-IQ) were detected. In conclusion, hydrogen peroxide in the physiological/pathological concentration range may be able to support the metabolic activation of arylamines to genotoxic products through the cytochrome P450 peroxygenase pathway.

  DOI：

  10.1021/tx960144k