At least two different polymorphisms in the human CYP1A1 gene have been associated with an increased risk for tobacco-related lung cancer; however, the functional significance of these polymorphisms has not been determined. We measured CYP1A1 genotypes, gene expression levels and enzymatic activity levels in mitogen-stimulated lymphocytes to determine whether genetic polymorphisms in CYP1A1 alter transcriptional and/or post-transcriptional regulation of the gene. Genotypes were determined at two sites previously associated with lung cancer: a point mutation in exon 7 near the catalytic region of the enzyme and an Mspl RFLP in the 3’ non-coding region of the gene. Variant genotypes at the Mspl site had no effect on CYPlAl gene induction, however, variant genotypes at the exon 7 site were significantly associated with Increased CYPlAl gene inducibility. We also observed a significant interaction between the exon 7 polymorphism and smoking on mRNA levels. There was a 3-fold elevation in CYP1A1 enzymatic activity in exon 7 variant genotypes. When Mspl and exon 7 genotypes were combined, there was an increased CYP1A1 inducibility and enzymatic activity in subjects with the exon 7 polymorphism, and in subjects with both polymorphisms.

Genetic susceptibility factors may play a role in determining adverse effects of exposure to environmental toxins. As a preliminary step to a molecular epidemiological study in a population exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD), we investigated 20 healthy Caucasian volunteers with a set of putative susceptibility markers including a CYP1A1 Msp I restriction fragment length genetic polymorphism (RFLP), CYP1A1 mRNA expression, and ethoxyresorufin-O-deethylase (EROD) activity in cultured and mitogen-activated blood lymphocytes. Both basal (p=0.008) and induced (p =0.0001) EROD activity was significantly higher among persons with a mutation in one or both alleles of the CYP1A1 gene (variant CYP1A1 genotype). Induction in vitro by TCDD significantly increased EROD activity in both variant and wild-type CYP1A1 subjects; however, the absolute increase was greater in subjects with variant genotypes. An additive interaction between genotype and TCDD induction was suggested. Expression of CYP1 Al mRNA, both basal and induced, did not vary significantly across the genotypes.

To estimate the relationship between air pollution and lung cancer, a nested case‐control study was set up within EPIC (European Prospective Investigation on Cancer and Nutrition). Cases had newly diagnosed lung cancer, accrued after a median follow‐up of 7 years among the EPIC exsmokers (since at least 10 years) and never smokers. Three controls per case were matched. Matching criteria were gender, age (±5 years), smoking status, country of recruitment and time elapsed between recruitment and diagnosis. We studied residence in proximity of heavy traffic roads as an indicator of exposure to air pollution. In addition, exposure to air pollutants (NO₂, PM10, SO₂) was assessed using concentration data from monitoring stations in routine air quality monitoring networks. Cotinine was measured in plasma. We found a nonsignificant association between lung cancer and residence nearby heavy traffic roads (odds ratio = 1.46, 95% confidence interval, CI, 0.89–2.40). Exposure data for single pollutants were available for 197 cases and 556 matched controls. For NO₂ we found an odds ratio of 1.14 (95% CI, 0.78–1.67) for each increment of 10 μg/m³, and an odds ratio of 1.30 (1.02–1.66) for concentrations greater than 30 μg/m³. The association with NO₂ did not change after adjustment by cotinine and additional potential confounders, including occupational exposures. No clear association was found with other pollutants.

Individual susceptibility to cancer from environmental agents may be influenced by polymorphic metabolic genes such as CYP1A1. The CYP1A1 gene contains four major polymorphisms identified to date. A modern nomenclature system, used with other genes, is presented to clarify the identity of these polymorphisms. The various CYP1A1 alleles exhibit population frequencies that depend on ethnicity. The association of these alleles with cancer at several sites has also been found to depend on racial or ethnic origin of the study population. Statistical considerations, such as the need for large studies when the power to detect a rare polymorphism is low, and ethnic differences in genetic linkage disequilibrium are among possible reasons for ethnic-specific effects on cancer susceptibility related to metabolic gene polymorphisms. New efforts to determine population frequencies of such polymorphisms are essential for future research in this area.