Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor.
Dehydroepiandrosterone (DHEA), the major precursor of androgens and estrogens, has several beneficial effects on the immune system, on memory function, and in modulating the effects of diabetes, obesity, and chemical carcinogenesis. Treatment of rats with DHEA influences expression of cytochrome P450 (P450) genes, including peroxisome proliferator-activated receptor alpha (PPAR alpha)- and pregnane X receptor (PXR)-mediated induction of CYP4As and CYP3A23, and suppression of CYP2C11. DHEA treatment elevated the expression and activities of CYP3A4, CYP2C9, CYP2C19, and CYP2B6 in primary cultures of human hepatocytes. Induction of CYP3A4 in human hepatocytes was consistent with studies in rats, but induction of CYP2Cs was unexpected. The role of PXR in this response was studied in transient transfection assays. DHEA activated hPXR in a concentration-dependent manner. Because CYP2B6 induction by DHEA in human hepatocytes might involve either PXR or constitutive androstane receptor (CAR) activation, we performed experiments in primary hepatocytes from CAR knockout mice and observed that CAR was required for maximal induction of Cyp2b10 by DHEA. Furthermore, CAR-mediated Cyp2b10 induction by DHEA was inhibited by the inverse agonist of CAR, androstanol (5 alpha-androstan-3 alpha-ol). Further evidence for CAR activation was provided by cytoplasmic/nuclear transfer of CAR upon DHEA treatment. Elucidation of CAR activation and subsequent induction of CYP2B6 by DHEA presented an additional mechanism by which the sterol can modify the expression of P450s. The effect of DHEA on the activation of the xenosensors PPAR alpha, PXR, and CAR, and the consequent potential for adverse drug/toxicant interactions should be considered in humans treated with this nutriceutical agent.
Kohalmy
Krisztina
K
Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary.
Tamási
Viola
V
Kóbori
László
L
Sárváry
Eniko
E
Pascussi
Jean-Marc
JM
Porrogi
Pálma
P
Rozman
Damjana
D
Prough
Russell A
RA
Meyer
Urs A
UA
Monostory
Katalin
K
D000328:Adult; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D000077297:Pregnane X Receptor; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D011987:Receptors, Steroid / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000187:drug effects*; D014162:Transfection; D014178:Translocation, Genetic / Q000235:genetics
D000090702:Constitutive Androstane Receptor; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D003687:Dehydroepiandrosterone; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating