QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) An erratum has been published All Versions of this Article: jpet.103.055798v1 308/1/300    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murayama, N. Articles by Sawada, J.-i. Search for Related Content PubMed PubMed Citation Articles by Murayama, N. Articles by Sawada, J.-i.

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Six Novel Nonsynonymous CYP1A2 Gene Polymorphisms: Catalytic Activities of the Naturally Occurring Variant Enzymes

Project Team for Pharmacogenetics (N.Mu., A.S., Y.S., Y.N., S.O., J.-i.S.), Division of Biochemistry and Immunochemistry (Y.S., J.-i.S.), Division of Pharmacology (S.O.), National Institute of Health Sciences, Tokyo, Japan; Departments of Cardiology (K.K., S.K., Ma.Ki.), Cardiovascular Dynamics Research Institute (K.K.), and Pharmacy (K.U.), National Cardiovascular Center, Osaka, Japan; National Institute of Neuroscience (H.K., Y.-i.G., N.Mi.); and National Center Hospital for Mental Nervous and Muscular Disorders (O.S., Ma.Ka., Te.O., Mi.Ka., K.S., Ta.O., C.S., N.Mi.), National Center for Neurology and Psychiatry, Tokyo, Japan

Six novel nonsynonymous nucleotide alterations were found in the cytochrome P450 1A2 gene in a Japanese population, which resulted in the following amino acid substitutions: T83M, E168Q, F186L, S212C, G299A, and T438I. These individuals were heterozygous for the amino acid substitutions. The potential functional alterations caused by the amino acid substitutions were characterized by a cDNA-mediated expression system using Chinese hamster V79 cells. Among the six CYP1A2 variants, F186L showed the most profound and statistically significant reduction in O-deethylation of phenacetin and 7-ethoxyresorufin. Kinetic analyses performed for the ethoxyresorufin O-deethylation revealed that the V_max of the F186L variant was approximately 5% of that of the CYP1A2 wild type, despite a 5-fold lower K_m value of the variant, the consequence of which was reduced enzymatic activity toward the substrate. Thus, for the first time, phenylalanine at residue 186 is suggested to be a critical amino acid for catalytic activity.

Address correspondence to: Dr. Shogo Ozawa, Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. E-mail: sozawa{at}nihs.go.jp

This article has been cited by other articles:

				J. A. Williams, T. Andersson, T. B. Andersson, R. Blanchard, M. O. Behm, N. Cohen, T. Edeki, M. Franc, K. M. Hillgren, K. J. Johnson, et al. PhRMA White Paper on ADME Pharmacogenomics J. Clin. Pharmacol., July 1, 2008; 48(7): 849 - 889. [Abstract] [Full Text] [PDF]

				K. L. Bigos, B. G. Pollock, K. C. Coley, D. D. Miller, S. R. Marder, M. Aravagiri, M. A. Kirshner, L. S. Schneider, and R. R. Bies Sex, Race, and Smoking Impact Olanzapine Exposure J. Clin. Pharmacol., February 1, 2008; 48(2): 157 - 165. [Abstract] [Full Text] [PDF]

				Y. Saito, N. Hanioka, K. Maekawa, T. Isobe, Y. Tsuneto, R. Nakamura, A. Soyama, S. Ozawa, T. Tanaka-Kagawa, H. Jinno, et al. FUNCTIONAL ANALYSIS OF THREE CYP1A2 VARIANTS FOUND IN A JAPANESE POPULATION Drug Metab. Dispos., December 1, 2005; 33(12): 1905 - 1910. [Abstract] [Full Text] [PDF]

				T. Kubo, S.-R. Kim, K. Sai, Y. Saito, T. Nakajima, K. Matsumoto, H. Saito, K. Shirao, N. Yamamoto, H. Minami, et al. FUNCTIONAL CHARACTERIZATION OF THREE NATURALLY OCCURRING SINGLE NUCLEOTIDE POLYMORPHISMS IN THE CES2 GENE ENCODING CARBOXYLESTERASE 2 (HCE-2) Drug Metab. Dispos., October 1, 2005; 33(10): 1482 - 1487. [Abstract] [Full Text] [PDF]

				C. Tang, J. H. Lin, and A. Y. H. Lu METABOLISM-BASED DRUG-DRUG INTERACTIONS: WHAT DETERMINES INDIVIDUAL VARIABILITY IN CYTOCHROME P450 INDUCTION? Drug Metab. Dispos., May 1, 2005; 33(5): 603 - 613. [Abstract] [Full Text] [PDF]