Glucocorticoids inhibit interconversion of 7-hydroxy and 7-oxo metabolites of dehydroepiandrosterone: a role for 11beta-hydroxysteroid dehydrogenases?
The cytochrome p450-dependent formation and subsequent interconversion of dehydroepiandrosterone (DHEA) metabolites 7 alpha-hydroxy-DHEA (7 alpha-OH-DHEA), 7 beta-hydroxy-DHEA (7 beta-OH-DHEA), and 7-oxo-DHEA was observed in human, pig, and rat liver microsomal fractions. Rat liver mitochondria and nuclei also converted DHEA to 7 alpha-OH-DHEA and 7-oxo-DHEA, but at a lower rate. With NADP(+), and less so with NAD(+), rat, pig, and human liver microsomes and rat liver mitochondria and nuclei converted 7 alpha-OH-DHEA to 7-oxo-DHEA. This reaction was inhibited by corticosterone and the 11 beta-hydroxysteroid dehydrogenase (11 betaHSD) inhibitor carbenoxolone (CBX). The conversion of 7 alpha-OH-DHEA to 7-oxo-DHEA by rat kidney occurred at higher rates with NAD(+) than with NADP(+) and was inhibited by corticosterone. With NADPH, 7-oxo-DHEA was converted to unidentified hydroxylated metabolites and low levels of 7 alpha-OH-DHEA by rat liver microsomes. In contrast, pig liver microsomal fractions reduced 7-oxo-DHEA to nearly equal amounts of 7 alpha- and 7 beta-OH-DHEA, while human fractions produced mainly 7 beta-OH-DHEA. Dehydrocorticosterone inhibited the reduction to both isomers by pig liver microsomes, but only to 7 alpha-OH-DHEA by human microsomes; CBX inhibited both reactions. Rat kidney did not reduce 7-oxo-DHEA with either NADPH or NADH. These results demonstrate that DHEA is first converted in liver to 7 alpha-OH-DHEA, which is subsequently oxidized to 7-oxo-DHEA in both liver and kidney. In liver, interconversion of 7-oxo-DHEA and 7-OH-DHEA isomers is largely catalyzed by 11 betaHSD1, while in kidney 11 betaHSD2 (NAD(+)-dependent) and 11 betaHSD3 (NADP(+)-dependent) likely catalyze the unidirectional oxidation of 7 alpha-hydroxy-DHEA to 7-oxo-DHEA. Distinct species-specific routes of metabolism of DHEA and the interconversion of its metabolites obviate extrapolation of animal studies to humans.
Robinzon
Boaz
B
Department of Biochemistry, University of Louisville Health Science Center, Louisville, KY 40292, USA.
Michael
Kristy K
KK
Ripp
Sharon L
SL
Winters
Stephen J
SJ
Prough
Russell A
RA
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D003345:Corticosterone / Q000494:pharmacology*; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D034421:Sus scrofa
D009243:NAD; C002914:7-oxodehydroepiandrosterone; D003687:Dehydroepiandrosterone; C003587:7-hydroxydehydroepiandrosterone; D009249:NADP; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D002229:Carbenoxolone; D003345:Corticosterone