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Vol. 62, Issue 3, 737-746, September 2002
Laboratories of Pharmacology & Chemistry (S.S.F., J.A.G.) and
Reproductive & Developmental Toxicology (M.N.), National Institute of
Environmental Health Sciences, Research Triangle Park, North Carolina;
and School of Pharmacy, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina (E.L.L.)
The CYP2C subfamily metabolizes many clinically important drugs. These
genes respond to prototypical inducers such as phenobarbital and
rifampicin, yet little has been reported on the mechanisms of
induction. This report examines the regulation of CYP2C9
with respect to two specific receptors thought to be involved in
phenobarbital (PB) induction, the constitutive androstane receptor
(CAR) and pregnane X receptor (PXR). Transfection of either mouse CAR
(mCAR) or human CAR (hCAR) into HepG2 cells results in increased
CYP2C9 mRNA content. Inducers further increased this response in
CAR transfected cells. mCAR but not hCAR conferred drug inducibility to
the proximal 
2145 bp of the CYP2C9 promoter in
luciferase assays. Further examination of a 2925-bp promoter
construct revealed that hCAR cotransfection increased activity 20-fold.
Gel shift assays confirmed the presence of a distal PB-responsive
enhancer module-like enhancer module, CAR-responsive enhancer (CAR-RE), between 2900 and 2841 bp consisting of two DR-5 nuclear receptor binding motifs capable of binding hCAR, mCAR, and, to a lesser extent,
human PXR. The majority of binding and hCAR activation is derived from
the NR1 portion of the CAR-RE. PB treatment did not further increase
the hCAR activation in any of the constructs. In summary, a new CAR/PXR
binding site was identified in the CYP2C9 promoter, and
this site seems to constitutively regulate transcription via a
CAR-dependent mechanism; however, it could not be shown to account for
PB inducibility of the gene.
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