The retinoic acid receptor‐related orphan receptor (ROR) regulates human CYP2C8

Abstract

Retinoic acid receptor-related orphan receptors (ROR)α, -β, and -γ are highly expressed in liver, brown fat, thymus and brain and are involved in many physiological processes such as circadian rhythm, lymph node development and immune function. Previous studies have identified liver genes like human ApoCIII and ApoAV as ROR targets. The cytochrome P450 (CYP) 2C enzymes metabolize many endogenous compounds and xenobiotics and are highly expressed in liver. To investigate whether RORs regulate the expression of the human CYP2Cs, we examined the possible transactivation of three human CYP2C promoters by RORs in HepG2 cells. We present the first evidence that ROR may induce transcription of human CYP2C8, which metabolizes both endogenous compounds and clinical drugs such as arachidonic acid, retinoic acid, paclitaxel, and certain diabetes drugs. Overexpression of RORγ and RORα in HepG2 cells significantly increased promoter activity of CYP2C8 but none of the RORs transactivated the promoters of CYP2C9 or CYP2C19. Computer analyses, promoter deletion studies, gel shift assays and mutational analysis identified a responsive element at −2045 bp in the CYP2C8 promoter which mediates RORγ transactivation. These data support a role of RORs in regulation of CYP2C8 expression in liver. This study was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences.