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FUNCTIONAL ANALYSIS OF SIX HUMAN ARYL HYDROCARBON RECEPTOR VARIANTS IN A JAPANESE POPULATION

Project Team for Pharmacogenetics (S.K., Y.S., H.F.-U., S.I., S.O., H.J., J.-I.S.), Division of Biochemistry and Immunochemistry (Y.S., J.-I.S.), Division of Pharmacology (S.I., S.O.), and Division of Environmental Chemistry (H.J.), National Institute of Health Sciences, Tokyo, Japan; Division of Genomic Medicine (N.K.), Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan; Division of Oncology/Hematology (H.M.), Division of GI Oncology/Digestive Endoscopy (A.O.), Deputy Director (N.S.), National Cancer Center Hospital East, Chiba, Japan; and Division of Internal Medicine (T.H., K.S.), National Cancer Center Hospital, Genetics Division (T.Y.), National Cancer Center Research Institute, National Cancer Center, Tokyo, Japan

Aryl hydrocarbon receptor (AhR) is an important transcriptional regulator involved in the induction of CYP1A1, CYP1A2, CYP1B1, UGT1A1, and UGT1A6. In this study, functional properties of four novel naturally occurring human AhR variants (K401R, N487D, I514T, and K17T/R554K) were examined along with the single variants K17T and R554K. The luciferase reporter assay using the CYP1A1 promoter reporter in HeLa cells treated with ß-naphthoflavone or 3-methylcholanthrene, which are known as typical agonists for AhR, showed that reporter activities of the K401R and N487D variants were reduced to 40 to 58% of those of wild-type (WT) but not of the other variants. Similarly, the K401R and N487D variants also reduced the omeprazole-induced reporter activities to approximately 56 and 74% of those of the WT, respectively. The reduced activities of the two variants were probably caused by the reduced protein expression levels, since the protein levels of the K401R and N487D variants were approximately 52 and 47% of the WT, respectively, without any changes in their mRNA levels. The reduced protein levels were recovered by treatment with a proteasome inhibitor MG132 [N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal], suggesting that the reduced protein levels were caused by the accelerated proteasomal degradation by a proteasome. Together, the current data demonstrate that the K401R and N487D variants reduce their apparent transcriptional activities, both ligand-induced and omeprazole-induced activation, probably through reduced protein expression. Thus, these two variants may influence drug metabolism through reduced induction of CYP1A1 and other target enzymes.

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