Progesterone oxidation by cytochrome P450 2D isoforms in the brain.
The existence of cytochrome P450 2D isoforms in the brain has been demonstrated, although their physiological functions remain to be elucidated. In this study we demonstrated that recombinant rat cytochrome P450 2D1 and 2D4 and human cytochrome P450 2D6 possess progesterone 6 beta- and 16 alpha- hydroxylation activities; 2 beta- and 21-hydroxylation activities; and 2 beta-, 6 beta-, 16 alpha- and 21-hydroxylation activities, respectively. Cytochrome P450 2D4 had the lowest K(m) value and the highest maximum velocity value toward these activities. Progesterone 2 beta- and 21-hydroxylation activities were also detected in rat brain microsomes, and these activities were completely inhibited by anticytochrome P450 2D antibodies. The presence of endogenous 2 beta- and 21-hydroxyprogesterones in rat brain tissues was also demonstrated. The mRNAs of cytochrome P450 2D4, CYP11A, and 3 beta-hydroxysteroid dehydrogenase were detected in the rat brain, suggesting that progesterone was generated from cholesterol by CYP11A and 3 beta-hydroxysteroid dehydrogenase and then underwent hydroxylation to hydroxyprogesterones by cytochrome P450 2D4 in rat brain. Collectively, our findings support the idea that cytochrome P450 2D may be involved in the regulation (metabolism and/or synthesis) of endogenous neuroactive steroids, such as progesterone and its derivatives, in brain tissues.
Hiroi
T
T
Department of Chemical Biology, Osaka City University Medical School, Osaka 545-8585, Japan. toyoko-loy@med.osaka-cu.ac.jp
Kishimoto
W
W
Chow
T
T
Imaoka
S
S
Igarashi
T
T
Funae
Y
Y
D000429:Alcohol Oxidoreductases; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001921:Brain / Q000378:metabolism*; D002384:Catalysis / Q000187:drug effects; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D003900:Desoxycorticosterone / Q000378:metabolism; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009420:Nervous System / Q000378:metabolism; D010084:Oxidation-Reduction; D011374:Progesterone / Q000031:analogs & derivatives / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000378:metabolism; D039181:Steroid 16-alpha-Hydroxylase; D013256:Steroids / Q000378:metabolism / Q000494:pharmacology
D004798:Enzymes; D011994:Recombinant Proteins; D013256:Steroids; D003900:Desoxycorticosterone; D011374:Progesterone; C088407:2-hydroxy-4-pregnene-3,20-dione; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000429:Alcohol Oxidoreductases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C450259:CYP2C8 protein, human; C504568:Cyp2d1 protein, rat; C115670:Cyp2d4 protein, rat; D065727:Cytochrome P-450 CYP2C8; D019389:Cytochrome P-450 CYP2D6; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase