RELATIONSHIPS BETWEEN GENETIC POLYMORPHISMS IN <I>CYP2D6</I> AND <I>CYP2E1</I> GENES AND LIVER MICROSOMAL DRUG OXIDATION ACTIVITIES:-STUDIES WITH 39 JAPANESE AND 45 CAUCASIANS-
スポンサーリンク
概要
- 論文の詳細を見る
Twenty one types of genetic polymorphisms in <I>CYP2D6</I> gene were determined in liver DNA of Japanese and Caucasians and compared these <I>CYP2D6</I> genotypes with CYP2D6 protein levels and bufuralol 1'- and 6-hydroxylation activities in liver microsomes of these human samples. We detected 11 types of <I>CYP2D6</I> genetic polymorphisms and classified these humans into 17 genotypes; 7 types were found in the Japanese and 13 types in the Caucasian. <I>CYP2D6*</I> <I>10B</I>, but not <I>CYP2D6*10A</I>, was the most frequent in mutation at 34.6% in the Japanese, whereas in Caucasians, <I>CYP2D6</I> polymorphisms including <I>CYP2D6*4A</I>, <I>*4D</I>, <I>*4E</I>, <I>*4L</I> <I>*3</I>, <I>*9</I>, and <I>*M12</I> (frequencies at 6.8, 3.4, 4.5, 9.1, 2.3, 2.3, 4.5%) respectively, were detected. A Caucasian having homozygous <I>CYP2D6*3/*3</I> had a protein with slower gel mobility (immunoblotting with anti-CYP2D6 antibody) and a very low activity for bufuralol 1'-hydroxylation. Five Caucasian samples with <I>CYP2D6*4A/*4A</I>, <I>*4A/*4L</I>, or <I>*4D/*4L</I> had no measurable CYP2D6 protein and very low bufuralol 1'-hydroxylation activities. Seven Japanese subjects with CYP2D6*10B/*IOB had CYP2D6 protein at levels of -20% of those present in humans with <I>CYP2D6*1</I> and <I>*2</I> and catalyzed bufuralol 1'-hydroxylation at low rates. These results support the view that <I>CYP2D6*3</I>, <I>*4A</I>, <I>*4D</I>, and <I>*4L</I> are major genotypes in producing poor metabolizer phenotypes in CYP2D6 in Caucasians, whereas <I>CYP2D6*10B</I> is a major causes in decreasing CYP2D6 protein expression and catalytic activities in Japanese. We also determine three types of <I>CYP2E1</I> genetic polymorphisms, namely RsaI/PstI-, DraI-, and MspI-types, and compared these genotypes with levels of CYP2E1 and activities of 7-ethoxycoumarin <I>O</I>-deethylation and chlorzoxazone 6-hydroxylation in liver microsomes from these human samples. The results obtained collectively indicated that <I>Rsa</I>I/<I>Pst</I>I-, <I>Dra</I>I-, and <I>Msp</I>I-types of <I>CYP2E1</I> polymorphisms may not cause significant alterations in protein expression and enzyme catalytic activities of CYP2E1 enzyme in human livers.
- 日本薬物動態学会の論文
日本薬物動態学会 | 論文
- COMPETITIVE DISPLACEMENT OF SERUM PROTEIN BINDING TO REGULATE PHARMACOKINETICS OF A CEREBRAL BLOOD FLOW RADIOPHARMACEUTICAL
- Studies on the Metabolic Fate of Felodipine. (IV). Identification of New Metabolites of Felodipine in Rat.
- Metabolic Fate of Pergolide Mesylate. (2): Absorption, Distribution, Excretion of 14C-Pergolide Mesylate in Rats after Repeated Administration.
- Studies on the Metabolic Fate of 3H-TJN-101. (III): Absorption, Distribution and Excretion after Multiple Oral Administration to Rats.
- Studies on the Pharmacokinetics of Perindopril Erbumine in Rats. (1): Plasma Level Profile, Distribution, Metabolism and Excretion after Single Oral Administration.