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P450 CYP1A2ノックアウトマウスにおける4-aminobiphenyl (ABP) および2-amino-1-methyl-6-pheny-limidazo [4,5-b] pyridine (PhIP)の発癌性の検討：河部真弓², Pedro FERNANDEZ-SALGUERO², Jerrold M.WARD¹, and Frank J. GONZALEZ² (¹Veterinary and Tumor Pathology Section, National Cancer Inst., ²Laboratory of Metabolism, National Cancer Inst.)

Carcinogenic Effects of 4-aminobiphenyl (ABP) and 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) in the P450 CYP1A2-knockout Mouse : Mayumi KAWABE¹, Pedro FERNANDEZ-SALGUERO², Jerrold M. WARD¹, and Frank J. GONZALEZ² (¹Veterinary and Tumor Pathology Section, National Cancer Inst., ²Laboratory of Metabolism, National Cancer Inst.)

It is known that PhIP, a heterocyclic amine and ABP are metabolically activated primarily by CYP1A2 in rat and mouse liver. To assess the susceptibility of the CYP1A2-knockout mouse to ABP and PhIP carcinogenicity using the neonatal mouse bioassay, ABP and PhIP were i.p. injected 600 and 1200 nmol (total dose) at 8 and 15 days of age, and mice were maintained until 16 (ABP) or 19 (PhIP) months. Treatment with ABP induced foci, adenoma of the liver in both low and higher dose groups. However, no differences in either genotype or by dose were shown. Hepatocellular carcinomas were also observed in male mice. In PhIP study, the incidences of malignant lymphoma were higher in the CYP1A2-knockout female mice than those of the wild type mice. In both ABP and PhIP studies, epithelial cell hyperplasia in the glandular stomach regardless of chemical dose, were observed, and the incidences were significantly increased in CYP1A2-knockout mice, especially female mice. Severe epithelial cell hyperplasia was accompanied by eosinophilic cytoplasmic inclusion bodies. These results indicated that specific lesions including eosinophilic inclusion bodies were induced in mice lacking CYP1A2 expression. N-OH ABP and N-OH PhIP, genotoxic metabolites of ABP and PhIP, respectively, were detected in CYP1A2-knockout mouse liver microsomes. These data suggest that a CYP1A2-independent pathway of metabolism of ABP may be involved.