Chemical carcinogenesis and cytochrome P450: carcinogenic aromatic amine-induced P450 and hepatocarcinogenic susceptibility to the aromatic amine in the rodent

Abstract

The N-hydroxyl and/or N-acetoxy derivatives of carcinogenic 4-aminoazo dyes, which were thought to be proximate and ultimate metabolites, were synthesized in our laboratory in 1975, and their chemical and biological characteristics were further examined. The results strongly supported the hypothesis that the metabolic conversions, N-hydroxylation and its O-acylation, of carcinogenic aromatic amines are important processes for their carcinogenicity. Carcinogenic aromatic amines such as heterocyclic aromatic amines and aminoazo dyes induced predominantly cytochrome P450IA2 (CYP1A2), which is responsible for the mutagenic activation and N-hydroxylation of the amines in the rodent. The induction rate and total activity of this enzyme were well correlated with sex, species, and target organ differences in hepatocarcinogenic susceptibility of animals to the aromatic amines. During hepatocarcinogenic process with an aromatic amine, the expression and induction of CYP1A2 decreased especially in preneoplastic liver cells as judged by the expression of a placental form of glutathione S-transferase.