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FUNCTIONAL CHARACTERIZATION OF FOUR NATURALLY OCCURRING VARIANTS OF HUMAN PREGNANE X RECEPTOR (PXR): ONE VARIANT CAUSES DRAMATIC LOSS OF BOTH DNA BINDING ACTIVITY AND THE TRANSACTIVATION OF THE CYP3A4 PROMOTER/ENHANCER REGION

Project Team for Pharmacogenetics (S.Ko., K.Ku., Y.S., S.O., J.-I.S.), Divisions of Medicinal Safety Science (K.Ku., R.H.), Biochemistry and Immunochemistry (Y.S., J.-I.S.), and Pharmacology (S.O.), National Institute of Health Sciences, Tokyo, Japan; Division of Cardiology (K.Ko., S.Ka., M.K.), Departments of Cardiovascular Dynamics Research Institute (K.Ko.) and Pharmacy (K.U.), National Cardiovascular Center, Suita, Japan; and Department of Allergy and Immunology, National Research Institute for Child Health and Development (T.N., K.M., H.S.) and Department of Pediatrics, National Children's Medical Center (A.A.), National Center for Child Health and Development, Tokyo, Japan

Metabolism of administered drugs is determined by expression and activity of many drug-metabolizing enzymes, such as the cytochrome P450 (P450s) family members. Pregnane X receptor (PXR) is a master transcriptional regulator of many drug/xenobiotic-metabolizing enzymes, including P450s and drug transporters. In this study, we describe the functional analysis of four naturally occurring human PXR (hPXR) variants (R98C, R148Q, R381W, and I403V) that we have recently identified. By a reporter gene assay using the CYP3A4 promoter/enhancer reporter in COS-7 or HepG2 cells, it was found that the R98C variant failed to transactivate the CYP3A4 reporter. The R381W and I403V variants also showed varying degrees of reduction in transactivation, depending on the dose of PXR activators, rifampicin, clotrimazole, and paclitaxel. The transcriptional activities of the R148Q variant were not significantly different from that of the wild-type hPXR. The electrophoretic mobility shift assay revealed that only the R98C variant lacked DNA binding. Furthermore, the cellular localization of the hPXR proteins was analyzed. All four variants as well as the wild-type hPXR localized exclusively to the nucleus, regardless of the presence or absence of rifampicin. These data suggest that the R98C, R381W, and I403V hPXR variants, especially R98C, may influence the expression of drug-metabolizing enzymes and transporters, which are transactivated by PXR.

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