EXPRESSION OF CYTOCHROME-P450 2A5 IN PRENEOPLASTIC AND NEOPLASTIC MOUSE-LIVER LESIONS

Cytochrome P450 (CYP) 2A5 is involved in the metabolism of carcinogens like aflatoxin B-1 and N-nitrosodiethylamine (NDEA), and CYP2A5 level s are increased in some pathological states of the liver (e.g., infect ious hepatitis and porphyria). We analyzed the expression of CYP2A5 du ring experimental liver carcinogenesis in three different mouse strain s (C3H/He, C57BL/6J, and B6C3F1) with immunohistochemical techniques a nd in situ hybridization. in normal liver, CYP2A5 protein and mRNA wer e detected in centrilobular hepatocytes only. Phenobarbital treatment increased the number of CYP2A5-positive centrilobular hepatocytes and the CYP2A5-positive areas were extended into the middle zone in all st rains, but periportal hepatocytes remained negative. Fifty percent of the spontaneous foci in untreated mice, over 90% of the foci in mice t reated with NDEA or phenobarbital and all of the hepatocellular adenom as and carcinomas displayed positive immunostaining and a strong CYP2A 5 mRNA signal by in situ hybridization. In the liver tumors metastasiz ed to the lung, expression of CYP2A5 had largely disappeared. CYP2A5 e xpression in neoplastic a nd putative preneoplastic lesions, although sometimes heterogeneous, was apparently independent of the typical zon al expression pattern in normal tissue. As expected, the C57BL/6J mice developed fewer foci and tumors than the C3H/He and B6C3F1 mice, but the phenotype of CYP2A5 overexpression was similar in all the strains. Our data suggest that the increased expression of CYP2A5 may play an important role in the development of liver cancer in mice and may be u sed as a novel marker for spontaneous and NDEA-induced mouse liver foc i. Mel. Carcinog. 22:229-234, 1998. (C) 1998 Wiley-Liss, Inc.