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 2alpha-/16alpha-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 omega-1-hydroxylation and testosterone 6beta-, 7alpha- and 17alpha-hydroxylations were less pronounced. 2. 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. 3. Northern analysis revealed a selective decrease in CYP4A2 mRNA expression in vitamin A-deficient rat liver to approximately 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. 4. 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. 5. From these studies it emerges that CYP4A2, a fatty acid omega-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.
Murray
M
M
Molecular Pharmacology Unit, Heart Research Institute, Camperdown, NSW 2052, Australia. M.Murray@unsw.edu.au
Sefton
R M
RM
Croft
K D
KD
Butler
A M
AM
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D013006:Growth Hormone / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013347:Subcellular Fractions / Q000201:enzymology; D013739:Testosterone / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000201:enzymology* / Q000378:metabolism
D000728:Androgens; D007527:Isoenzymes; D012333:RNA, Messenger; D016718:Arachidonic Acid; D013739:Testosterone; D013006:Growth Hormone; D003577:Cytochrome P-450 Enzyme System