Significance of polymorphisms in human xenobiotic metabolising enzymes

Abstract: Cigarette smoke is the primary cause of lung cancer but urban air pollution and certain occupational exposures have also been found to elevate the incidence of lung cancer. These exposures contain polycyclic aromatic hydrocarbons (PAH), which can be metabolically activated to highly reactive compounds capable of binding to DNA and initiating the carcinogenic process unless they are eliminated. Interindividual variation in the capacity to activate and eliminate PAH is expected to modulate the individual response to PAH exposures. Different allelic variants (genetic polymorphisms) have been described for several xenobiotic metabolising enzymes including cytochrome P4501AI (CYP1A1), glutathione transferase M1, P1 and T1 (GSTM1/P1/T1), microsomal epoxide hydrolase (mEH) and NAD(P)H:quinone oxidoreductase I (NQO1). In the biomonitoring and epidemiological studies presented in this thesis, susceptibility markers, in terms of well-characterised genetic polymorphisms in biotransformation enzymes, were included in order to improve the precision of carcinogen exposure and health risk estimates. In the studies on lung cancer risk, 524 lung cancer patients and 530 healthy control subjects of Swedish origin constituted the study population. Lung cancer patients with the CYP1A1('1/'2A, '2A/'2A, '1/'2B), NQO1('1/'2, '2/'2) and GSTM1('0/'0) variant genotypes were suggested to have an increased risk for certain histological subtypes. Stratification by cumulative smoking dose indicated that the risks associated with the CYP1A1 and GSTM1 variant genotypes were restricted to light smokers. In contrast, the GSTT1 '0/'0 genotype appeared to confer protection against lung cancer of all main histological subtypes in heavy smokers. Genetic susceptibility markers were also applied in the studies of potroom workers in a Swedish aluminum production plant. Ninety-eight workers and 55 unexposed control subjects participated. No significantly elevated levels in any of the genotoxic markers used were found but urinary 1-hydroxypyrene (1-OHP) levels, the internal dose marker, correlated significantly with airborne PAH levels. The aluminum workers carrying the CYP1A1 and GSTM1 variant genotypes showed the highest levels of urinary 1-OHP, whereas those with the GSTT1 '0/'0 genotype had lower levels of 1-OHP in urine. Thus, individuals with the CYP1A1 and GSTM1 variant genotypes appeared to have an increased susceptibility to PAH as shown by overrepresentation of these genotypes among smokers with certain lung cancer subtypes and the increased levels of urinary 1OHP after occupational PAH exposure. Another interesting finding was that individuals with the GSTT1 '0/'0 genotype appeared to be less sensitive to PAH as they were underrepresented among patients of all main histological subtypes and had decreased levels of 1-OHP when occupationally exposed to PAR The trimodal distribution of GSTT1 activity measured with methyl chloride in erythrocytes was found to be explained by a recently identified GSTT1 deletion polymorphism (GSTT1 '0). The concordance between the GSTT1 phenotypes and genotypes was very high. A novel polymorphism in the GSTT1 gene (GSTT1 'B) associated with the non-conjugator phenotype was subsequently identified. Further characterisation indicated that this novel allele results in an unstable protein. By including analysis for the novel GSTT1 polymorphism, the accuracy in predicting the GSTT1 phenotype was improved.