INCREASED EXPRESSION OF THE FEMALE-PREDOMINANT CYTOCHROME P4502C12 IN LIVER NODULES FROM MALE WISTAR RATS

Nodules and hepatomas from male and female rats treated according to the resistant hepatocyte (RH) model were analyzed with respect to expression of the male-predominant cytochrome P4502C11 (P450(16alpha)) and the female-predominant cytochrome P4502C12 (P450(15beta)) at the transcriptional and at the mRNA and protein levels. In male nodules isolated 8 and 11 to 12 months after initiation and in hepatomas, the expression of P450(16alpha) mRNA was 3- to 11-fold lower than in surrounding liver, whereas a 2- to 8-fold higher expression of P450(15beta) was observed compared with surrounding tissue. These alterations in P450 mRNA expression were reflected by similar changes at the protein level. Nuclear transcription of the cytochrome P450(16alpha) gene was lower in male nodules than in surrounding liver whereas transcription of the P450(15beta) gene was higher in the nodules. In nodules and hepatomas from female rats no significant differences in either mRNA expression or protein level of either P450(16alpha) or P450(15beta) were seen. The present study indicates that liver nodules are, to some extent, withdrawn from the normal endocrine regulation of rat liver function. Furthermore, the observed increase in a specific cytochrome P450 species (P450(15beta)) in male liver nodules contradicts the previous suggestion of a general downregulation of this enzyme family as a characteristic of the nodular phenotype.