Pierre Dayer

An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians.

The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans. This polymorphism exhibits marked racial heterogeneity, with the poor metabolizer PM phenotype representing 13-23% of oriental populations, but only 2-5% of Caucasian populations. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) have been described, which account for more than 99% of Oriental poor metabolizer alleles but only approximately 87% of Caucasian poor metabolizer alleles. Therefore, additional defects presumably contribute to the poor metabolizer in Caucasians. Recent studies have found a third mutation CYP2C19*4, which accounts for approximately 3% of Caucasian poor metabolizer alleles. A fourth rare mutation (CYP2C19*5A) (C99,A991,Ile331;C1297T,Arg433-->Trp) resulting in an Arg433 to Trp substitution in the heme-binding region has been reported in a single Chinese poor metaboliser outlier belonging to the Bai ethnic group. The present study identifies a second variant allele CYP2C19*5B (C99-->T; A991-->G, Ile331-->Val; C1297-T, Arg433-->Trp in one of 37 Caucasian poor metabolizers. The frequency of the CYP2C19*5 alleles is low in Chinese (approximately 0.25% in the Bai ethnic group) and Caucasians (< 0.9%). However, these alleles contribute to the poor metabolizer phenotype in both ethnic groups and increases the sensitivity of the genetic tests for identifying defective alleles to approximately 100% in Chinese poor metabolizers and 92% in Caucasian poor metabolizers genotyped in our laboratory. The Arg433 to Trp mutation in the heme-binding region essentially abolishes activity of recombinant CYP2C19*5A toward S-mephenytoin and tolbutamide, which is consistent with the conclusion that CYP2C19*5 represents poor metabolizer alleles.

N-acetyltranferase NAT1 and NAT2 genotypes and lung cancer risk

Acetyltransferases, encoded by the NAT1 and NAT2 genes, are involved in the activation/inactivation reactions of numerous xenobiotics, including tobacco-derived aromatic amine carcinogens. Several allelic variants of NAT1 and NAT2, which cause variations in acetylation capacity, have been detected. The NAT2 slow acetylator phenotype/genotype has been inconsistently associated with lung cancer and, to date, the role of NAT1 polymorphism in lung cancer has not been reported. The effect of NAT1 and NAT2 genetic polymorphisms on individual lung cancer risk was evaluated among 150 lung cancer patients and 172 control individuals, all French Caucasian smokers. The NAT1 alleles (*3, *4, *10, *11, *14, and *15) and the NAT2 alleles (*4, *5, *6, *7) were differentiated by polymerase chain reaction-based restriction fragment length polymorphism methods using DNA extracted from peripheral white blood cells. Genotypes were classified according to current knowledge of the functional activity of the variant alleles. The NAT1*10 and NAT1*11 alleles were considered as rapid alleles, the NAT1*4 and the NAT1*3 as normal alleles and NAT1*14 and NAT1*15 as slow-acetylation alleles. Logistic regression analyses were performed taking into account the age, sex, smoking and occupational exposures. A significant association was observed between lung cancer and NAT1 genotypes (P(homogeneity) < 0.02) with a gene dose effect (P(trend) < 0.01); compared with homozygous rapid acetylators, the lung cancer risk was 4.0 (95% confidence interval 0.8-19.6) for heterozygous rapid acetylators, 6.4 (95% confidence interval 1.4-30.5) for homozygous normal acetylators and 11.7 (95% confidence interval 1.3-106.5) for heterozygous slow acetylators. None of the individuals were homozygous slow acetylators. Similar results were obtained whatever the adjustment considered. No significant association was found between NAT2 genotype and lung cancer. The NAT1 polymorphism may thus be an important modifier of individual susceptibility to smoking-induced lung cancer.

CYP1A1 genetic polymorphisms, tobacco smoking and lung cancer risk in a French Caucasian population.

The CYP1A1 gene encoding for an enzyme involved in the metabolic activation of important tobacco carcinogens could be implicated in smoking-induced lung cancer. Given the strong association between tobacco smoking and lung cancer, the effect of tobacco smoke exposure has to be taken into account when studying the potential association between lung cancer and CYP1A1 genotypes. The effect of two CYP1A1 genetic polymorphisms (Mspl and IIe-Val) on lung cancer risk were evaluated using peripheral blood DNA from 150 lung cancer patients and 171 controls. The Mspl sitepresent allele was found among 19.3% of both cases and controls and the variant allele Val among 6.7% of cases and 8.8% of controls. Lung cancer risks associated with the Mspl site-present allele (OR= 0.9; 95%Cl: 0.5-1.8) or with the Val allele (OR= 0.8; 95%Cl: 0.3-1.9) were not increased after adjustment for tobacco and asbestos exposures. These results persisted when analyses were stratified on smoking status, daily consumption of tobacco or duration of smoking. Similar findings were obtained when squamous cell or small cell carcinomas were studied separately. This study thus suggests a minor role for the known CYP1A1 gene polymorphisms in predisposition to lung cancer among Caucasian populations.