No abstract

Abstract. CYP1A1 and CYP1B1 are involved in the metabolism of carcinogens. The effect of CYP1A1 and CYP1B1 polymorphisms as genetic modifiers of risk was investigated in individuals with asbestos, silica dust or ionizing radiationinduced occupational tumours compared to exposed non-cancer subjects suffering from pneumoconiosis, particularly in relation to tobacco smoking. CYP1A1 T6235C, CYP1A1 A4889G and CYP1B1 codon 432 polymorphisms were determined by realtime Pcr analysis in patients with asbestos-related lung cancer (n=39), patients with diffuse malignant mesotheliomas (n=19), lung cancer in silicosis patients (n=7), uranium miners with lung cancer (uMlc) (n=40), patients with asbestosis (n=181), and silicosis patients (n=204). The results were compared to those from a healthy unexposed control group (n=50) not exposed to carcinogenic (or fibrogenic) agents in the workplace. an additional healthy control group (n=134) comprised smokers and ex-smokers. allele frequencies were within the range described for caucasians. Multivariate analysis revealed that patients with occupational diseases with the susceptible CYP1A1 T6235C genotype had a calculated risk ranging from or=0.5 (95% ci 0.18-1.36) for uMlc to or=1.23 (95% ci 0.39-4.05) for uranium miners with silicosis. The risk for patients with the susceptible CYP1A1 A4889G allele was calculated as being between or=0.39 (95% ci 0.10-1.54) for mesothelioma patients and or=1.54 (95% ci 0.49-4.89) for uMlc. CYP1B1 Val432Leu polymorphisms were associated with a risk of or=0.56 (95% ci 0.2-1.55) for uMlc and or=1.52 (95% ci 0.68-3.39) for asbestos-exposed lung cancer patients. By analyzing the interaction between tobacco smoking, type of exposure to carcinogens and the genotypes, it was determined that smoking and the presence of the susceptible genotypes did not have a combined effect. in this pilot study, the analyzed polymorphism had no consistent modifying effect on pneumoconiosis or occupationally related tumours. Introductionindividual differences in susceptibility to occupationally induced carcinomas are in part ascribed to genetic differences in metabolic activity regarding the activation or detoxification of environmental carcinogens. Human lung cancer is caused by exposure to carcinogens such as polycyclic aromatic hydrocarbons (PaH), found mainly in cigarette smoke, but can also be caused by exposure to carcinogens in the workplace, such as asbestos, ionizing radiation or silica dust.Most environmental carcinogens require metabolic activation by Phase i enzymes, cytochrome P-450s, to their reactive electrophilic intermediates. Several forms of P-450 have been identified. CYP1A1 is involved in the bioactivation of carcinogenic PaH. in a caucasian population, an association was found between CYP1A1 homozygous Mspi rFlP and lung cancer (1,2).In vitro studies have demonstrated that asbestos fibres exert a destructive effect through the generation of reactive oxygen species (roS), which leads to alterations in mitochondrial function and the activation of several...