Differential regulation of endobiotic‐oxidizing cytochromes P450 in vitamin A‐deficient male rat liver

The hepatic CYP4A‐dependent ω‐hydroxylation of arachidonic acid and CYP2C11‐dependent 2α‐/16α‐hydroxylations of testosterone were decreased to 74 and 60% of respective control in microsomal fractions from vitamin A‐deficient rats. Decreases in the rates of arachidonic acid ω‐1‐hydroxylation and testosterone 6β‐, 7α‐ and 17α‐hydroxylations were less pronounced. Corresponding decreases in microsomal CYP4A and CYP2C11 immunoreactive protein expression to 64 and 68% of respective control were observed in vitamin A‐deficient rat liver. Expression of CYP3A proteins was unchanged from vitamin A‐adequate control. Northern analysis revealed a selective decrease in CYP4A2 mRNA expression in vitamin A‐deficient rat liver to ∼5% of control; expression of the related CYP4A1/4A3 mRNAs was not decreased. CYP2C11 mRNA expression was also decreased in vitamin A‐deficient male rat liver to 39% of control levels. Intake of the deficient diet containing all‐ trans ‐retinoic acid (ATRA) during the final week of the experiment restored CYP4A2 mRNA and CYP4A protein. Administration of exogenous androgen or episodic growth hormone was ineffective. In contrast, CYP2C11 expression was restored by ATRA and androgen, but not by growth hormone. From these studies it emerges that CYP4A2, a fatty acid ω‐hydroxylase in rat liver, is highly dependent on vitamin A for optimal expression, whereas CYP2C11 is indirectly down regulated by androgen deficiency resulting from vitamin A‐deficiency. Altered CYP expression in vitamin A‐deficiency provides insights into the relationship between dietary constituents and the intracellular formation of vasoactive eicosanoids as well as the clearance of androgenic steroids.British Journal of Pharmacology (2001) 134 , 1487–1497; doi: 10.1038/sj.bjp.0704380