Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor.

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Kohalmy K, Tamasi V, Kobori L, Sarvary E, Pascussi JM, Porrogi P, Rozman D, Prough RA, Meyer UA, Monostory K

Dehydroepiandrosterone induces human CYP2B6 through the constitutive androstane receptor.

Drug Metab Dispos. 2007 Sep;35(9):1495-501. Epub 2007 Jun 25.

PubMed ID

17591676 [ View in PubMed

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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 (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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Prasterone	Nuclear receptor subfamily 1 group I member 2	Protein	Humans	Unknown	Activator	Details
Prasterone	Nuclear receptor subfamily 1 group I member 3	Protein	Humans	Unknown	Activator	Details
Prasterone	Peroxisome proliferator-activated receptor alpha	Protein	Humans	Unknown	Activator	Details