Metabolism of pravastatin sodium by 3 alpha-hydroxysteroid dehydrogenase.
When incubated with isolated rat hepatocytes, pravastatin sodium (PS) yielded a small amount of a metabolite in addition to two major metabolites that have already been reported. The previously uncharacterized metabolite was found to be formed by at first being enzymatically dehydrogenated to 6'-keto intermediate (R-104), followed by decomposition to give the aromatized metabolite (R-195), through spontaneous deesterification with accompanying aromatization. The PS-6'beta-hydroxydehydrogenase activity was localized in cytosolic fraction and required NADP, preferentially over NAD, as a cofactor. The formation of R-195 by rat liver cytosol was strongly inhibited by indomethacin, 3 alpha-hydroxysteroids (but not 3 beta-isomers) and 3-ketosteroids. The results and high substrate specificity of purified PS-6'beta-hydroxydehydrogenase toward 3 alpha-hydroxysteroids suggested that the enzyme is identical to 3 alpha-hydroxysteroid dehydrogenase.
Muramatsu
S
S
Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Komokata
Y
Y
Tanaka
Y
Y
Takahagi
H
H
D015096:3-Hydroxysteroid Dehydrogenases / Q000302:isolation & purification / Q000378:metabolism*; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D004591:Electrophoresis, Polyacrylamide Gel; D008099:Liver / Q000166:cytology / Q000201:enzymology*; D017035:Pravastatin / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D015096:3-Hydroxysteroid Dehydrogenases; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); D017035:Pravastatin