The inhibition of rat adrenal cytochrome P-45011 beta gene expression by androgens.
The synthetic androgen methylandrostenediol (MAD) and the naturally occurring one, testosterone, both bring about hypertensive cardiovascular disease when chronically administered to rats. The pathogenesis of this form of experimental hypertension is thought to result from inhibition of steroid 11 beta-hydroxylase activity. In contrast to the above androgens, 19-nortestosterone, androstenedione and dehydroepiandrosterone (DHEA) have been reported to be without effect in elevating blood pressure. To examine the mechanism(s) involved, we have in this study compared the effects of a number of androgens on adrenal cytochrome P- 45011 beta enzyme and mRNA steady state levels. These parameters were also correlated with the ability of adrenal mitochondria isolated from these groups to hydroxylate 11-deoxycorticosterone (DOC) to corticosterone and 18-hydroxy-11-deoxycorticosterone (18-hydroxy-DOC). Rats treated for seven days with 10 mg per day of dihydrotestosterone, testosterone, 19-nortestosterone or MAD showed a profound decrease in cytochrome P-45011 beta mRNA levels (to less than 20% of controls). This was accompanied by similar changes in both the level and activity of the enzyme. Androstenedione and DHEA were less potent in effecting these changes. In addition, for MAD and testosterone we tested the dose dependence of these changes and found that increasing doses (0.1 mg to 10 mg per day) of either androgen caused progressive decreases in the parameters measured. To assess selectivity we also determined the steady state level of cytochrome P-450scc mRNA in rats treated with the various androgens. In contrast to what was found with cytochrome P-45011 beta, the mRNA transcript for cytochrome P-450scc was equal to or above control levels. We conclude that, in general, the extent of inhibition of cytochrome P-45011 beta enzyme and mRNA level by a given androgen correlates with its reported facility in producing hypertension in rats. Increased secretion of DOC continues to be a likely mechanism for the development of this hypertension but with some androgens extra-adrenal effects may be involved.
Gallant
S
S
Department of Biochemistry, State University of New York, School of Medicine and Biomedical Sciences, Buffalo 14214.
Alfano
J
J
Charpin
M
M
Brownie
A C
AC
D000311:Adrenal Glands / Q000201:enzymology*; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D019405:Cytochrome P-450 CYP11B2; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D012313:RNA / Q000302:isolation & purification; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000378:metabolism; D045165:Testosterone Congeners / Q000494:pharmacology*
D000728:Androgens; D012333:RNA, Messenger; D045165:Testosterone Congeners; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme