Turesky R J, Constable A, Richoz J, Varga N, Markovic J, Martin M V, Guengerich F P
Nestlé Research Center, Nestec Ltd., Vers-chez-les-Blanc, 1000 Lausanne 26, Switzerland.
Chem Res Toxicol. 1998 Aug;11(8):925-36. doi: 10.1021/tx980022n.
The dietary mutagens 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are activated to genotoxins by rat and human liver cytochrome P450 (P450) 1A1- and 1A2-mediated N-oxidation. Immunoquantitation of 51 human liver samples revealed a wide range in P450 1A2 expression (10-250 pmol/mg of microsomal protein, median 71 pmol/mg), with 39% of the livers containing >100 pmol/mg of protein. There was no evidence for expression of P450 1A1 (<1 pmol/mg of protein). P450 1A2 levels were correlated to MeIQx and PhIP N-oxidation rates (r = 0.83, 0.73, respectively). In male Fischer-344 and Sprague-Dawley rats, hepatic P450 1A2 ranged from 5 to 35 pmol/mg of protein, while P450 1A1 was <1 pmol/mg. Animal pretreatment with 3-methylcholanthrene, beta-naphthoflavone, or polychlorinated biphenyls (PCB) resulted inasmuch as 340-fold and >1000-fold induction of P450 1A2 and 1A1, respectively, and a 220-fold increase in N-oxidation activity. Approximately 20% of the human samples were as active in N-oxidation and conversion of MeIQx to bacterial mutagens as microsomes of PCB-pretreated rats [3-4 nmol of NHOH-MeIQx formed min-1 (mg of protein)-1]. In contrast, microsomes from PCB-treated rats displayed higher rates of PhIP N-oxidation and activation to mutagens than the most active human liver microsomes [8-24 vs 2-4 nmol of HNOH-PhIP formed min-1 (mg of protein)-1]. Recombinant human P450 1A2 showed catalytic efficiencies of MeIQx and PhIP N-oxidation that were 10-19-fold higher than purified rat P450 1A2. Cytochrome P450 1A2 expression in rodent and human liver tissue varies greatly and there are considerable differences between the enzymes in the two species in the activation of some heterocyclic aromatic amines, which must be considered when assessing human health risk.
膳食诱变剂2-氨基-3,8-二甲基咪唑并[4,5-f]喹喔啉（MeIQx）和2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）通过大鼠和人肝脏细胞色素P450（P450）1A1和1A2介导的N-氧化作用被激活成为基因毒素。对51份人肝脏样本进行免疫定量分析发现，P450 1A2的表达水平差异很大（微粒体蛋白含量为10 - 250 pmol/mg，中位数为71 pmol/mg），39%的肝脏样本中该蛋白含量>100 pmol/mg。未发现P450 1A1有表达（蛋白含量<1 pmol/mg）。P450 1A2水平与MeIQx和PhIP的N-氧化速率相关（相关系数分别为0.83和0.73）。在雄性Fischer-344和Sprague-Dawley大鼠中，肝脏P450 1A2含量为5 - 35 pmol/mg蛋白，而P450 1A1<1 pmol/mg。用3-甲基胆蒽、β-萘黄酮或多氯联苯（PCB）对动物进行预处理后，P450 1A2和1A1的诱导倍数分别高达340倍和>1000倍，N-氧化活性增加了220倍。约20%的人肝脏样本在N-氧化以及将MeIQx转化为细菌诱变剂方面的活性与经PCB预处理的大鼠微粒体相当[形成NHOH-MeIQx的速率为3 - 4 nmol·min⁻¹·(mg蛋白)⁻¹]。相比之下，经PCB处理的大鼠微粒体对PhIP的N-氧化和激活成为诱变剂的速率高于活性最高的人肝脏微粒体[形成HNOH-PhIP的速率分别为8 - 24 nmol·min⁻¹·(mg蛋白)⁻¹和2 - 4 nmol·min⁻¹·(mg蛋白)⁻¹]。重组人P450 1A2对MeIQx和PhIP的N-氧化催化效率比纯化的大鼠P450 1A2高10 - 19倍。啮齿动物和人肝脏组织中细胞色素P450 1A2的表达差异很大，在激活某些杂环芳香胺方面，这两种物种的酶存在显著差异，在评估人类健康风险时必须考虑这些因素。
