The ontogeny of cytochrome P450 4A (CYP4A) gene expression in the rat.

Cytochrome P450s (P450s) play a major role in the metabolism of endogenous and exogenous chemicals. P450-metabolism generally converts compounds into more hydrophilic derivatives, which can then be excreted. In contrast, it can lead to the formation of reactive intermediates, which can attack cellular macromolecules leading to mutagenesis. The cytochrome P450 4A (CYP4A) subfamily encodes proteins involved in lipid metabolism. The CYP4A1, CYP4A2 and CYP4A3 genes are expressed constitutively in the adult rat, elevated expression being seen after administration of a hypolipidemic drug, clofibrate. The interest in the CYP4A subfamily is partly related to the apparent close association between CYP4A1 induction and the phenomenon of sustained peroxisome proliferation. It is also believed that the CYP4A proteins may be involved in the production of physiologically important renal metabolites. The aim of this thesis was a systematic study of the ontogeny and inducibility of CYP4A1 mRNA and protein levels in embryonic, fetal and post-natal rats. Constitutive and induced hepatic expression of the CYP4A1, CYP4A2 and CYP4A3 mRNAs was demonstrated in the 24 day, 10.5 day and day 1 neonates, in addition to the 18.5 day fetal expression. Renal expression was not detected prenatally, and was only apparent in the day 1 neonates following induction. The mRNAs were also present in induced adult brown fat; induced and control adult and 24 day neonatal small intestine; induced 18.5 day fetal placenta and, induced and control 11.5 day embryonic decidua. The demonstration of inducible CYP4A1 gene expression is potentially important, as in conjunction with peroxisome proliferation, it may result in an increased susceptibility of the tissue to carcinogenesis. The P450 inductive response may also play an important role in elevating the rate of metabolism of foreign compounds to detoxified forms, or in some cases to harmful reactive intermediates. If this were to occur during pregnancy it could potentially have important consequences for the developing embryo/fetus.