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First published on June 25, 2007; DOI: 10.1124/dmd.107.016303

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Received for publication April 17, 2007.
Revised June 16, 2007.
Accepted for publication June 18, 2007.

Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor

Krisztina Kohalmy 1, Viola Tamasi 2, Laszlo Kobori 3, Eniko Sarvary 3, Jean-Marc Pascussi 4, Palma Porrogi 1, Damjana Rozman 5, Russell A. Prough 6, Urs A. Meyer 2, Katalin Monostory 1*

1 Chemical Research Center, Hungarian Academy of Sciences 2 Biocenter of the University of Basel 3 Transplantation and Surgical Clinic, Semmelweis University 4 INSERM U632, Universite Montpellier 5 University of Ljubljana 6 University of Louisville

* Address correspondence to: E-mail: monostor{at}chemres.hu

Abstract

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 (CYP) 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. As CYP2B6 induction by DHEA in human hepatocytes might involve either PXR or CAR (constitutive androstane receptor) 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. 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 CYPs. 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.


Key words: CAR, CYP expression, CYP induction, CYP2B, CYP2C, CYP3A, isolated hepatocytes, PXR, steroids, transcriptional regulation




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