CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice
CYP1A2 is not the primary enzyme responsible for 4-aminobiphenyl-induced hepatocarcinogenesis in mice
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DOI：
10.1093/carcin/20.9.1825
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发表时间：
1999-09-01
期刊：
影响因子：
4.7
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
Kimura, S;Kawabe, M;Gonzalez, FJ
4-氨基联苯（4-ABP）是啮齿动物（肝癌）和人类（膀胱癌）的一种强致癌物，被发现是一种环境污染物和烟草烟雾。在吸烟者中发现了3-ABP的血红蛋白加合物和肺DNA加合物。人和大鼠肝微粒体的体外代谢研究表明，CYP 1A 2主要负责催化N-羟基化，这是4-ABP代谢活化的初始步骤。为了确定P450是否是肝癌发生的限速途径，在16月龄时分析CYP 1A 2-null小鼠，并将其对4-羟色胺的反应与野生型小鼠进行比较。ABP使用新生小鼠生物测定法和两种不同剂量的致癌物。基因型或4-ABP剂量之间肝细胞腺瘤、癌和癌前病灶发生率的总体差异不显著，而特定类型病灶的差异较小，但具有显著性。这些结果表明，虽然CYP 1A 2水平可能不是4-ABP代谢产生肿瘤和病灶的速率限制，它可能以积极或消极的方式调节某些类型肝灶的诱导过程。使用CYP 1A 2无效和野生型小鼠肝微粒体进行的体外研究显示，CYP 1A 2不是4-ABP N-羟基化所需的唯一P450，可能涉及另一个P450（尚未鉴定）。
4-Aminobiphenyl (4-ABP), a potent carcinogen in rodents (liver cancer) and human (bladder cancer), is found as an environmental contaminant and in tobacco smoke. Hemoglobin adducts and lung DNA adducts of 3-ABP are found in tobacco smokers. In vitro metabolism studies with human and rat liver microsomes have shown that CYP1A2 is primarily responsible for catalyzing N-hydroxylation, the initial step in the metabolic activation of 4-ABP, To determine whether this P450 is a rate limiting pathway for hepatocarcinogenesis, CYP1A2-null mice were analyzed at 16 months of age and were compared with wild-type mice in their response to 4-ABP using the neonatal mouse bioassay and two different doses of the carcinogen. Overall differences in incidences of hepatocellular adenoma, carcinoma and preneoplastic foci were not significant between either genotypes or 4-ABP doses used, whereas small, but significant, differences were found for specific types of foci, These results suggest that while CYP1A2 levels may not be rate limiting for 4-ABP metabolism to produce tumors and foci, it may modulate the induction process of some types of liver foci in either a positive or negative manner. In vitro studies using CYP1A2-null and wild-type mouse liver microsomes revealed that CYP1A2 is not the sole P450 required for 4-ABP N-hydroxylation and that another, yet to be identified, P450 is likely to be involved.