Selective and potent inhibitors of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) that metabolizes neurosteroids derived from progesterone.
Neuroactive steroids, such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) and 3alpha,5alpha-tetrahydrodeoxycorticosterone have been shown to be synthesized from progesterone in animal brains. Comparison of kinetic constants for the neuroactive steroids and their precursors among four human 3(20)alpha-hydroxysteroid dehydrogenases (AKR1C1-AKR1C4) suggests that AKR1C1 and AKR1C2 are involved in the catabolism and synthesis, respectively, of the neuroactive steroids in the human brain. In our efforts to identify agents that would specifically inhibit the two enzymes, benzbromarone and 3',3",5',5"-tetrabromophenolphthalein were found to be relatively selective and potent inhibitors of AKR1C1. Kinetic analyses in the oxidoreduction catalyzed by AKR1C1 in the presence of the inhibitors suggest that the inhibitors bind to the enzyme-NADP(H) complex (K(i)=0.7 nM) in the ordered bi-bi pathway, including an isomerization step. The inhibitors effectively also decreased the reduction of 3alpha,5alpha-THP to its 20alpha-hydroxy metabolite in HepG2 cells treated with ethacrynic acid.
Higaki
Yu
Y
Laboratory of Biochemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, 502-8585, Gifu, Japan.
Usami
Noriyuki
N
Shintani
Syunichi
S
Ishikura
Shuhei
S
El-Kabbani
Ossama
O
Hara
Akira
A
D015089:20-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D001553:Benzbromarone / Q000494:pharmacology*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D010635:Phenolphthaleins / Q000494:pharmacology*; D011374:Progesterone / Q000378:metabolism*
D004791:Enzyme Inhibitors; D010635:Phenolphthaleins; D011374:Progesterone; D001553:Benzbromarone; D015089:20-Hydroxysteroid Dehydrogenases; C115140:3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase; C018156:3',3'',5',5''-tetrabromophenolphthalein