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Male F344 rats were treated with lead nitrate and changes in the expression and induction of P450IA subfamily enzymes and a placental form of glutathione-S-transferase (GST-P) in the liver were assessed by means of a bacterial mutation test, immunoblotting with a monoclonal antibody reactive to P450IA1/IA2 and anti-GST-P sera and Northern blotting with P450IA2 cDNA as a probe. Treatment of rats with lead nitrate (20, 50 or 100 μmol/kg body wt) decreased P450IA2 mRNA and protein in the liver in the dose-dependent fashion and also decreased the microsomal activity for P450IA2-dependent mutagenization of aromatic amines. Pretreatment of rats with lead nitrate suppressed the inductions of both P450IA2 mRNA and protein by an inducer of P450IA subfamily enzymes in the liver. In addition, amount of the induced P450IA2 was decreased along with increase in that of the induced GST-P. [ABSTRACT FROM PUBLISHER]

The change of cytochrome P450 (P450) isozymes in a early stage of hepatocarcinogenesis in male F344 rats has been studied. Liver microsomes were prepared from normal rats (group 1), rats treated with diethylnitrosamine (DEN) alone, which developed no hyperplastic nodules (group 2), and rats treated with DEN plus 2-acetylaminofluorene, which developed many hyperplastic nodules (group 3). The amount and activity of P450IA1 and P450IA2 expressed in the liver were analyzed by several immunological methods using monoclonal antibodies against the P450 isozymes and a mutagenicity test. In the group 2 and 3 rats, the total amount of P450 and the amount of P450IA2 were much smaller than those in the group 1 rats, and P450IA1 was detected only from the group 3 rats. As observed by immunohistochemistry, P450IA1 was prominent in hyperplastic nodules developed in the group 3 rats, and the distribution of P45OIA1 cells in individual nodules was heterogeneous. When the rats were treated with a P450 inducer, 3-methoxy-4-aminoazobenzene or 3-methylcholanthrene, both P450IA1 and P450IA2 were induced in all groups of rats; however, the induction rates of the P450 isozymes, especially that of P450IA2, in the group 3 rats were smaller than those in the group 1 and 2 rats. The present work demonstrated that P450IA1, which is responsible mainly for detoxication of aromatic amine carcinogens, increased in level along with the development of hyperplastic nodules, whereas P450IA2, which is responsible for mutagenic or carcinogenic activation of these carcinogens, decreased in its amount and inducibility. [ABSTRACT FROM PUBLISHER]