Regulation of CYP26 (cytochrome P450RAI) mRNA expression and retinoic acidmetabolism by retinoids and dietary vitamin A in liver of mice and rats

Retinoic acid (RA), through nuclear retinoid receptors, regulates the expre ssion of numerous genes. However, little is known of the biochemical mechan isms that regulate RA concentration in vivo. CYP26 (P450RAI), a novel cytoc hrome P450, is expressed during embryonic development, induced by all-trans RA, and capable of catalyzing the oxidation of [H-3]RA to polar retinoids including 4-oxo-RA. Here we report that CYP26 expression in adult liver is regulated by all-trans RA and dietary vitamin A, and is correlated with the metabolism of all-trans RA to polar metabolites. In normal mouse and rat l iver, CYP26 mRNA was barely detectable; however, after acute treatment with all-trans RA CYP26 mRNA and RA metabolism by liver microsomes were signifi cantly induced. Aqueous-soluble RA metabolites were detected, but their for mation was not induced. The expression of retinoid receptors, RAR-gamma and RXR-alpha, was not changed after RA treatment in vivo. In a model of chron ic vitamin A ingestion during aging, CYP26 mRNA expression, determined by N orthern blot and RT-PCR analysis, increased progressively with dietary vita min A (P<0.0001; marginal < control < supplemented) and age (P<0.003). The relative expression of CYP26 mRNA was positively correlated with liver tota l retinol (log(10)), ranging from undetectable CYP26 expression at liver re tinol concentrations below similar to 20 nmol/g to a three- to fourfold ele vation at concentrations >10,000 nmol/g (r=0.90, P<0.0001). We conclude tha t CYP26 expression and RA metabolism are regulated in adult liver not only acutely by RA administration, as may be relevant to retinoid therapy but un der chronic dietary conditions relevant to vitamin A nutrition in humans.