METABOLIC CYTOCHROME-P450 GENOTYPES AND ASSESSMENT OF INDIVIDUAL SUSCEPTIBILITY TO LUNG-CANCER

被引：42

作者：

HIRVONEN, A ^{[1
]}

HUSGAFVELPURSIAINEN, K ^{[1
]}

ANTTILA, S ^{[1
]}

KARJALAINEN, A ^{[1
]}

SORSA, M ^{[1
]}

VAINIO, H ^{[1
]}

机构：

[1] INT AGCY RES CANC,F-69372 LYON,FRANCE

来源：

PHARMACOGENETICS | 1992年 / 2卷 / 06期

关键词：

D O I：

10.1097/00008571-199212000-00003

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Three polymorphic cytochrome P450 genes that have attracted interest for their potential role in human pulmonary carcinogenesis, i.e. CYP1A1, CYP2D6 and CYP2E1, were studied in a population consisting of 106 lung cancer patients and 122 healthy controls. Polymorphism of the CYP2D6 gene encoding for debrisoquine hydroxylase was determined using Xba I restriction fragment length polymorphism (RFLP) analysis together with a PCR based method. All of the three most common presently known defective alleles of CYP2D6 were detected by this application. Subjects having genotypes either homozygous or heterozygous for the CYP2D6 wild type alleles were classified as extensive metabolizers (EMs) of debrisoquine whereas poor metabolizers (PMs) had two defective allales. The PM individuals are thought to be less prone to develop lung cancer. The CYP1A1 and CYP2E1 genes were studied by RFLP analyses using Msp I and Dra I restriction enzymes, respectively, giving rise to two different sized hybridizable fragments in Southern blot analyses. In these RFPL analyses genotypes homozygous to the mutated allele have been presented as potent determinants of individual lung cancer risk. In the present study no association between polymorphic CYP1A1 and CYP2E1 genotypes and susceptibility to lung cancer was found. However, CYP2D6 polymorphism studies of the 122 healthy controls revealed seven poor metabolizer genotypes (5.7%), which compares well with the previously observed phenotypic distribution in the Finnish population, whereas only one PM genotype (1/106) was found among the lung cancer patients. These results agree with the previous suggestions that PMs of debrisoquine are less susceptible to lung cancer than EMs.

引用

页码：259 / 263

页数：5

共 30 条

[1] Arvela P., Kirjarinta M., Kirjarinta M., Karki N., Pelkonen O., Polymorphism of debrisoquine hydroxylation among Finns and Lapps, Br J Clin Pharmacol, 26, pp. 601-603, (1988)
[2] Caporaso N., Landli M., Vineis P., Relevance of metabolic polymorphisms to human carcinogenesis: Evaluation of epidemiologic evidence, Pharmacogenetics, 1, pp. 4-19, (1991)
[3] Church G.M., Gilbert W., Genomic sequencing, Proc Natl Acad Sci USA, 81, pp. 1991-1995, (1984)
[4] Daly A.K., Armstrong M., Monkman S.C., Idle M.E., Idle J.F., Genetic and metabolic criteria for the assignment of debrisoquine 4-hy- droxylation (Cytochrome P4502D6) phenotypes, Pharmacogenetics, 1, pp. 33-41, (1991)
[5] Gough A.C., Miles J.S., Spurr N.K., Moss J.E., Gaedigk A., Eichelbaum M., Wolf R.C., Identification of the primary gene defect at the cytochrome P450 CYP2D6 locus, Nature (Lond), 347, pp. 773-776, (1990)
[6] Gonzalez F.J., Skoda R.C., Kimura A., Umeno M., Zanger U.M., Nebert D.W., Gelboin H.V., Hardwick J.P., Meyer U.A., Characterization of the common genetic defect in humans deficient in debrisoquine metabolism, Nature, 331, pp. 442-446, (1988)
[7] Guengerich F.P., Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy, Cancer Res, 48, pp. 2946-2954, (1988)
[8] Hayashi S., Watanabe J., Nakachi K., Kawajiri K., Genetic linkage of lung cancer-associated Msp I polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P450IA1 gene, J Biochem, 110, pp. 407-411, (1991)
[9] Hayashi S., Watanabe J., Kawajiri K., Genetic polymorphisms in the 5'-flanking region change transcriptional regulation of the human cytochrome P450IIE1 gene, J Biochem, 110, pp. 559-565, (1991)
[10] Heim M., Meyer U.A., Genotyping poor metabolizers of debrisoquine by allele-specific PCR amplification, Lancet, 336, pp. 529-532, (1990)

← 1 2 3 →