TY - JOUR T1 - Six Novel Nonsynonymous <em>CYP1A2</em> Gene Polymorphisms: Catalytic Activities of the Naturally Occurring Variant Enzymes JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 300 LP - 306 DO - 10.1124/jpet.103.055798 VL - 308 IS - 1 AU - Norie Murayama AU - Akiko Soyama AU - Yoshiro Saito AU - Yukiko Nakajima AU - Kazuo Komamura AU - Kazuyuki Ueno AU - Shiro Kamakura AU - Masafumi Kitakaze AU - Hideo Kimura AU - Yu-ichi Goto AU - Osamu Saitoh AU - Masaaki Katoh AU - Teiichi Ohnuma AU - Mitsuru Kawai AU - Kenji Sugai AU - Taisuke Ohtsuki AU - Chieko Suzuki AU - Narihiro Minami AU - Shogo Ozawa AU - Jun-ichi Sawada Y1 - 2004/01/01 UR - http://jpet.aspetjournals.org/content/308/1/300.abstract N2 - 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 Vmax of the F186L variant was approximately 5% of that of the CYP1A2 wild type, despite a 5-fold lower Km 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. The American Society for Pharmacology and Experimental Therapeutics ER -