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The genetic susceptibility hypothesis has been used to explain why only a minority of smokers develop lung cancer. Only few studies have studied the role of polymorphisms in phase-I and II metabolizing genes, among young lung cancer patients. We have pooled the individual data of three studies from Denmark and Norway, including 320 patients diagnosed with non-small cell lung cancer at age 59 or below, and 618 age and gender matched controls. A questionnaire was used to determine relevant demographic and lifestyle characteristics, and polymorphisms in following genotypes were determined GSTM1, GSTM3, GSTP1, GSTT1, GPX1, MPO, NQO1 and NAT2. Based on the literature, the alleles of the genotypes were categorised as high- or low-risk alleles. No individual effect of the genotypes was found on the risk of lung cancer. Given a smoking exposure, the presence of high-risk alleles (or phenotypes) was generally found to increase the risk of lung cancer, although the effect modification did not reach statistical significance. A pattern of stronger protective effect was observed in carriers of more than one allele associated with lower risk of lung cancer, and a higher risk of lung cancer in carriers of one or more alleles associated with higher risk of lung cancer, but the results did not reach statistical significance. The effect modification was generally strongest at lower levels of smoking.

Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

The development of prostate cancer is dependent on heredity, androgenic influences, and exposure to environmental agents. A high intake of dietary fat is associated with an increased risk of prostate cancer, either through influence on steroid hormone profiles or through production of carcinogenic compounds that require biotransformation by enzymes. The polymorphic glutathione S-transferase (GST), N-acetyltransferase (NAT), and cytochrome P450 (CYP) enzymes are of particular interest in prostate cancer susceptibility because of their ability to metabolize both endogenous and exogenous compounds, including dietary constituents. Association between different NAT2, CYP2D6, CYP2C19 and GSTP1 genotypes and prostate cancer was studied in a Swedish and Danish case-control study comprising 850 individuals. The combined Swedish and Danish study population was analysed by polymerase chain reaction for the NAT2 alleles *4, *5A, *5B, *5C, *6 and *7, and for the CYP2D6 alleles *l, *3 and *4. The Swedish subjects were also analysed for the CYP2C19 alleles *1 and *2, and the GSTP1 alleles *A, *B and *C. No association was found between prostate cancer and polymorphisms in NAT2, CYP2D6, CYP2C19 or GSTP1. An association between CYP2D6 poor metabolism and prostate cancer was seen among smoking Danes; odds ratio 3.10 (95% confidence interval 1.07; 8.93), P = 0.03, but not among smoking Swedes; odds ratio 1.19 (95% confidence interval 0.41; 3.42), P = 0.75. Smoking is not a known risk factor for prostate cancer, and the association between CYP2D6 poor metabolism and prostate cancer in Danish smokers may have arisen by chance.

The metabolism of tobacco carcinogens was studied in a potential target for their carcinogenic effects. Rat buccal mucosa cells metabolized several polycyclic aromatic hydrocarbons, e.g., benzo(a)pyrene, benz(b)- and benz(j)-fluoranthene, dibenz(a,j)acridine, N,N-diethylnitrosamine and protein pyrolysate products, 2-amino-3-methylimidazo(4,5-f)quinoline, and 2-amino-3,4-dimethylimidazo(4,5-f)quinoline, as measured by binding of the carcinogens to cellular DNA. The highest level of binding was seen with the nitrosamine followed by the protein pyrolysate products. There was no significant difference in the binding levels between the different polycyclic aromatic hydrocarbons. Cells treated with a non-cytotoxic dose of the non-volatile condensate fraction of regular tobacco smoke increased metabolism as measured by binding to DNA of the protein pyrolysate products, whereas the pretreatment did not have any effect on the metabolism of benzo(a)pyrene, and N,N-diethylnitrosamine. However, the profile of benzo(a)pyrene metabolites released into the media changed. The results indicate that rat buccal mucosa cells metabolize several classes of tobacco specific carcinogens, and that the metabolism is modified by continued exposure to tobacco smoke components.