Species differences in the biotransformation of the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by hepatic microsomes and cytosols from humans, rats, and mice.
Species differences in the biotransformation of the food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine by hepatic microsomes and cytosols from humans, rats, and mice.
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人类、大鼠和小鼠的肝微粒体和细胞质对食源性致癌物 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶进行生物转化的物种差异。
DOI：
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发表时间：
1995
影响因子：
3.9
通讯作者：
F. Kadlubar
中科院分区：
文献类型：
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作者：
D. Lin;N. Lang;F. Kadlubar
对食源性致癌物2-amino-1-methyl-6-phenylimidazo[4，5-b]pyridine(PhIP)在人、大鼠和小鼠肝脏亚细胞部分的代谢活化和解毒作用进行了比较研究，以阐明基因毒性和致癌作用的种间差异和器官特异性差异的机制。PhIP分别与人、大鼠和小鼠肝微体孵育产生两种代谢物，分别被鉴定为N-羟基-PhIP和4‘-羟基-PhIP。然而，这些代谢物的形成速度在物种之间存在显著差异。人肝微粒体将PhIP转化为遗传毒性代谢物N-羟基-PhIP的能力最强，其平均+/-SD值(9.69+/-5.15nmol/mg蛋白/30min，N=3)分别是大鼠(5.25+/-1.63，N=3)和小鼠(6.89+/-0.55，N=3)的1.8倍和1.4倍。啮齿动物微粒体也能将PhIP转化为其非遗传毒性的4‘-羟基衍生物；然而，这一解毒途径在人类肝微粒体中可以忽略不计。人、大鼠和小鼠的N-羟化和4‘-羟化的比例分别为97：1、3.3：1和1.7：1。以胞浆O-乙酰转移酶、磺基转移酶、L-脯氨酰-tRNA合成酶和三磷酸腺苷依赖的激酶(S)进一步代谢活化N-羟基-苯丙氨酸的能力为生物活化的指标。用人和啮齿动物肝细胞浆检测到N-羟基苯丙氨酸的乙酰辅酶A依赖的DNA结合，并显示出显著的种间差异。
A comparative study on the metabolic activation and detoxification of the food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), by human, rat, and mouse hepatic subcellular fractions was conducted to elucidate the mechanism of the interspecies and organ-specific differences in genotoxicity and carcinogenesis. Incubation of PhIP with human, rat, and mouse hepatic microsomes each generated two metabolites, which were identified as N-hydroxy-PhIP and 4'-hydroxy-PhIP. However, the rates of formation of these metabolites differed significantly between species. Human hepatic microsomes had the highest capacity to convert PhIP to the genotoxic metabolite, N-hydroxy-PhIP, with a mean +/- SD value (9.69 +/- 5.15 nmol/mg protein/30 min, N = 3) that was 1.8-fold and 1.4-fold higher than that of rats (5.25 +/- 1.63, N = 3) and mice (6.89 +/- 0.55, N = 3) p < 0.05), respectively. Rodent microsomes were also able to convert PhIP to its nongenotoxic 4'-hydroxy derivative; however, this detoxification pathway was negligible in human hepatic microsomes. The ratio of N-hydroxylation to 4'-hydroxylation was 97:1, 3.3:1, and 1.7:1 for humans, rats, and mice, respectively. The capacities for the further metabolic activation of N-hydroxy-PhIP by cytosolic O-acetyltransferase, sulfotransferase, L-prolyl-tRNA synthetase, and an ATP-dependent kinase(s) were examined using PhIP-DNA binding as a measure of bioactivation. Acetyl coenzyme A-dependent DNA binding of N-hydroxy-PhIP was detected with both human and rodent hepatic cytosols, and showed a significant interspecies difference.(ABSTRACT TRUNCATED AT 250 WORDS)