Neurosteroid metabolism. 7 alpha-Hydroxylation of dehydroepiandrosterone and pregnenolone by rat brain microsomes.
Two 'neurosteroids', dehydroepiandrosterone (DHEA) and pregnenolone (PREG), are converted by rat brain microsomes into polar metabolites, identified as the respective 7 alpha-hydroxylated (7 alpha-OH) derivatives by the 'twin ion' technique of g.l.c.-m.s. with deuterated substrates. The enzymic reaction requires NADPH and is stimulated 2-4-fold by EDTA. Under optimal conditions (pH 7.4, 0.5 mM-NADPH, 1 mM-EDTA), the Km values for DHEA and PREG are 13.8 and 4.4 microM respectively, and the Vmax. values are 322 and 38.8 pmol/min per mg of microsomal protein respectively. Trace amounts of putative 7 beta-OH derivatives of DHEA and PREG are detected. Oestradiol, at a pharmacological concentration of 5 microM, inhibits DHEA and PREG 7 alpha-hydroxylation. Formation of 7 alpha-hydroxylated metabolites is low in prepubertal rats and increases 5-fold in adults. Derivatives of PREG and DHEA, such as PREG sulphate, DHEA sulphate, progesterone and 3 alpha-hydroxy-5 alpha-pregnan-20-one, are known to be neuroactive. Therefore the quantitatively important metabolism to 7 alpha-OH compounds may contribute to the control of neurosteroid activity in brain.
Akwa
Y
Y
Unité 33 INSERM, Lab Hormones, Bicetre, France.
Morfin
R F
RF
Robel
P
P
Baulieu
E E
EE
D006907:17-alpha-Hydroxypregnenolone / Q000037:antagonists & inhibitors / Q000378:metabolism; D000375:Aging / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D006900:Hydroxylation; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011284:Pregnenolone / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D004967:Estrogens; D006907:17-alpha-Hydroxypregnenolone; D003687:Dehydroepiandrosterone; C003587:7-hydroxydehydroepiandrosterone; D011284:Pregnenolone; D006899:Mixed Function Oxygenases