Developmental Aspects of P450iiia: Prenatal Activity and Inducibility

Abstract

We have used antiserum of defined specificity as well as a specific inducers and inhibitors of P450IIIA1(2) to determine the fetal occurrence and inducibility of this enzyme in rats. Apparently absent from uninduced fetal rat liver (or present in extremely low amounts) cytochrome P450IIIA1(2) becomes increasingly inducible as a function of gestational age. In adult rats, it is now apparent that there are at least two inducible members and one male-specific constitutive member of the IIIA subfamily. The ontogenesis of these enzymes from 2 weeks post partum to puberty has also been determined. The male-specific occurrence of P450IIIA2 subject to testosterone imprinting and maintenance has been proposed. Inconsistencies persist, however. Waxman et al. have proposed the perinatal occurrence in male and female rats with subsequent suppression in females, whereas others have not detected P450IIIA1(2) in uninduced perinatal rat liver. These differences remain unresolved and reflect the difficulties in defining the individual enzyme specificities for various substrates and of antiserum reactivity. Approaches recently applied to investigations of the IIB subfamily of cytochromes P-450 should contribute greatly to the elucidation of factors governing the ontogenesis of IIIA in rats and humans. Recently, cDNA probes capable of discriminating P450IIB1 and P450IIB2 (commonly referred to as P450s b and e, respectively) were utilized to discriminate the developmental regulation of these immune cross-reactive enzymes. cDNA probes specific for the constitutive and inducible P450IIIA enzymes should clarify the P450IIIA ontogeny in rats. However, in light of regulatory differences among the human and rat members of P450IIIA, it is apparent that the extrapolation of human biotransforming potential from results of animal models must be approached with great caution.