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

1 The hepatic CYP4A-dependent omega -hydroxylation of arachidonic acid and CYP2C11-dependent 2 alpha-/16 alpha -hydroxylations of testosterone were de creased to 74 and 60% of respective control in microsomal fractions from vi tamin A-deficient rats. Decreases in the rates of arachidonic acid omega -1 -hydroxylation and testosterone 6 beta-, 7 alpha- and 17 alpha -hydroxylati ons were less pronounced. 2 Corresponding decreases in microsomal CYP4A and CYP2C11 immunoreactive pr otein expression to 64 and 68% of respective control were observed in vitam in A-deficient rat liver. Expression of CYP3A proteins was unchanged from v itamin A-adequate control. 3 Northern analysis revealed a selective decrease in CYP4A2 mRNA expression in vitamin A deficient rat liver to similar to5% of control; expression of the related CYP4Al/4A3 mRNAs was not decreased. CYP2C11 mRNA expression wa s also decreased in vitamin A-deficient male rat liver to 39% of control le vels. 4 Intake of the deficient diet containing all-traps-retinoic acid (ATRA) du ring the final week of the experiment restored CYP4A2 mRNA and CYP4A protei n. Administration of exogenous androgen or episodic growth hormone was inef fective. In contrast, CYP2C11 expression was restored by ATRA and androgen, but not by growth hormone. 5 From these studies it emerges that CYP4A2, a fatty acid omega -hydroxylas e in rat liver, is highly dependent on vitamin A for optimal expression, wh ereas 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 th e intracellular formation of vasoactive eicosanoids as well as the clearanc e of androgenic steroids.