Science Links Japan | Relationships Between Genetic Polymorphisms in CYP2D6 and CYP2E1 Genes and Liver Microsomal Drug Oxidation Activities. Studies with 39 Japanese and 45 Caucasians.

Relationships Between Genetic Polymorphisms in CYP2D6 and CYP2E1 Genes and Liver Microsomal Drug Oxidation Activities. Studies with 39 Japanese and 45 Caucasians.

Accession number;00A0997668

Title;Relationships Between Genetic Polymorphisms in CYP2D6 and CYP2E1 Genes and Liver Microsomal Drug Oxidation Activities. Studies with 39 Japanese and 45 Caucasians.

Author; SHIMADA TSUTOMU (Osaka Prefect. Inst. of Public Health) TSUMURA FUJIKO (Osaka Prefect. Inst. of Public Health) YAMAZAKI HIROSHI (Osaka Prefect. Inst. of Public Health) GUENGERICH F P (Vanderbilt Univ., Tn) INOUE KIYOSHI (Osaka Prefect. Inst. of Public Health)

Journal Title;Xenobiotic Metabolism and Disposition

Journal Code:X0758A

ISSN:0916-1139

VOL.15;NO.Supplement;PAGE.S84-S85(2000)

Figure&Table&Reference;FIG.1

Pub. Country;Japan

Language;Japanese

Abstract;Twenty one types of genetic polymorphisms in CYP2D6 gene were determined in liver DNA of Japanese and Caucasians and compared these CYP2D6 genotypes with CYP2D6 protein levels and bufuralol 1'- and 6-hydroxylation activities in liver microsomes of these human samples. We detected 11 types of CYP2D6 genetic polymorphisms and classified these humans into 17 genotypes; 7 types were found in the Japanese and 13 types in the Caucasian. CYP2D6*10B, but not CYP2D6*10A, was the most frequent in mutation at 34.6% in the Japanese, whereas in Caucasians, CYP2D6 polymorphisms including CYP2D6*A4,*4D,*4E,*4L *3,*9, and *M12(frequencies at 6.8,3.4,4.5,9.1,2.3,2.3,4.5%) respectively, were detected. A Caucasian having homozygous CYP2D6*3/*3 had a protein with slower gel mobility(immunoblotting with antiCYP2D6 antibody) and a very low activity for bufuralol 1'-hydroxylation. Five Caucasian samples with CYP2D6*4A/*4A,*4A/*4L, or *4D/*4L had no measurable CYP2D6 protein and very low bufuralol 1'-hydroxylation activities. Seven Japanese subjects with CYP2D6*10B/*10B had CYP2D6 protein at levels of -20% of those present in humans with CYP2D6*1 and *2 and catalyzed bufuralol 1'-hydroxylation at low rates. These results support the view that CYP2D6*3, *4A,*4D, and *4L are major genotypes in producing poor metabolizer phenotypes in CYP2D6 in Caucasians, where CYP2D6*10B is a major causes in decreasing CYP2D6 protein expression and catalytic activities in Japanese. We also determine three types of CYP2E1 genetic polymorphisms, namely RsaI/PstI-,DraI-, and MspI-types, and compared these genotypes with levels of CYP2E1 and activities of 7-ethoxycoumarin O-deethylation and chlorzoxazone 6-hydroxylation in liver microsomes from these human samples. The results obtained collectively indicated that RsaI/PstI-,DraI-, and MspI-types of CYP2E1 polymorphisms may not cause significant alterations in protein expression and enzyme catalytic activities of CYP2E1 enzyme in human livers. (author abst.)

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