TY - JOUR
T1 - Glucocorticoids inhibit interconversion of 7-hydroxy and 7-oxo metabolites of dehydroepiandrosterone
T2 - A role for 11β-hydroxysteroid dehydrogenases?
AU - Robinzon, Boaz
AU - Michael, Kristy K.
AU - Ripp, Sharon L.
AU - Winters, Stephen J.
AU - Prough, Russell A.
PY - 2003/4/15
Y1 - 2003/4/15
N2 - The cytochrome P450-dependent formation and subsequent interconversion of dehydroepiandrosterone (DHEA) metabolites 7α-hydroxy-DHEA (7α-OH-DHEA), 7β-hydroxy-DHEA (7β-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 7α-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 7α-OH-DHEA to 7-oxo-DHEA. This reaction was inhibited by corticosterone and the 11β-hydroxysteroid dehydrogenase (11βHSD) inhibitor carbenoxolone (CBX). The conversion of 7α-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 7α-OH-DHEA by rat liver microsomes. In contrast, pig liver microsomal fractions reduced 7-oxo-DHEA to nearly equal amounts of 7α- and 7β-OH-DHEA, while human fractions produced mainly 7β-OH-DHEA. Dehydrocorticosterone inhibited the reduction to both isomers by pig liver microsomes, but only to 7α-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 7α-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 11βHSD1, while in kidney 11βHSD2 (NAD+-dependent) and 11βHSD3 (NADP+-dependent) likely catalyze the unidirectional oxidation of 7α-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.
AB - The cytochrome P450-dependent formation and subsequent interconversion of dehydroepiandrosterone (DHEA) metabolites 7α-hydroxy-DHEA (7α-OH-DHEA), 7β-hydroxy-DHEA (7β-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 7α-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 7α-OH-DHEA to 7-oxo-DHEA. This reaction was inhibited by corticosterone and the 11β-hydroxysteroid dehydrogenase (11βHSD) inhibitor carbenoxolone (CBX). The conversion of 7α-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 7α-OH-DHEA by rat liver microsomes. In contrast, pig liver microsomal fractions reduced 7-oxo-DHEA to nearly equal amounts of 7α- and 7β-OH-DHEA, while human fractions produced mainly 7β-OH-DHEA. Dehydrocorticosterone inhibited the reduction to both isomers by pig liver microsomes, but only to 7α-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 7α-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 11βHSD1, while in kidney 11βHSD2 (NAD+-dependent) and 11βHSD3 (NADP+-dependent) likely catalyze the unidirectional oxidation of 7α-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.
KW - 11β-Hydroxysteroid dehydrogenase
KW - 7-Oxo-DHEA
KW - 7α-Hydroxy-DHEA
KW - 7β-Hydroxy-DHEA
KW - Brain
KW - Corticosterone
KW - Dehydrocorticosterone
KW - Dehydroepiandrosterone
KW - Humans
KW - Kidney
KW - Liver
KW - Pig
KW - Rats
UR - http://www.scopus.com/inward/record.url?scp=0037445848&partnerID=8YFLogxK
U2 - 10.1016/S0003-9861(03)00056-0
DO - 10.1016/S0003-9861(03)00056-0
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C2 - 12667489
AN - SCOPUS:0037445848
SN - 0003-9861
VL - 412
SP - 251
EP - 258
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 2
ER -