Metabolic gene polymorphism frequencies in control populations.

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.

Polymorphisms in NAT2, CYP2D6, CYP2C19 and GSTP1 and their association with prostate cancer.

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.

Glutathione S-transferases as risk factors in prostate cancer.

Glutathione S-transferases are enzymes involved in the metabolism of carcinogens and in the defence against reactive oxygen species. Genetic polymorphisms have been detected in glutathione S-transferases M1, T1 and P1, and some of these polymorphisms have been associated with an increased risk of cancer. In a case-control study (153 cases and 288 controls) the effect of these genetic polymorphisms on the risk of prostate cancer was investigated. Homozygote deletion of either GSTM1 or GSTT1 was not associated with a statistically significant increased risk, odds ratio (OR) 1.3; 95% confidence intervals (CI) 0.9-1.9 and 1.3; 0.8-2.2, respectively. Deletion of both GSTM1 and GSTT1 gave a near-significant increased risk (OR 1.7; 95% CI 0.9-3.4). Two allelic variants of GSTP1 (codon 105) have been reported. This polymorphism was not linked to an increased risk (OR 0.8; 95% CI 0.5-1.1). Smokers that lack either GSTM1 or GSTT1 activity had a slightly higher risk of prostatic cancer than smokers expressing the genes, OR 1.4 (95% CI 0.6-3.3) and 1.6 (0.6-3.9), respectively. Our results show that differences in enzymes involved in the metabolism of carcinogens slightly modify prostate cancer risk, especially in people exposed to carcinogens that are detoxified by these enzymes.

Exposure to aflatoxin B1 in animal-feed production plant workers.

The exposure to aflatoxin B1 (AFB) in animal-feed processing plants was assessed using binding of AFB to serum albumin. The albumin fraction was digested with pronase, and the digest was purified on a C18 Sepak column and an aflatest affinity column before quantification by ELISA. The level of detectability was 5 pg/mg albumin. The workers served as their own controls, as blood samples were taken upon return from vacation and after 4 weeks of work. A total of 7 of 45 samples were positive for AFB, with an estimated average daily intake of 64 ng AFB/kg body weight. The exposed workers had been disembarking cargos contaminated with AFB or working at places where the dust contained detectable amounts of AFB. The sera from the exposed workers had a significantly higher titer against an aflatoxin B1-epitope than a nonexposed Danish control group. The level of exposure could partly explain the increased risk of liver cancer in workers in the animal-feed processing industry.

Detection of tobacco smoke carcinogen-DNA adducts in cultured rat buccal mucosa cells following exposure to ethanol and total cigarette smoke condensate or chewing tobacco.

Formation of carcinogen-DNA adducts in rat oral epithelial cells after treatment with cigarette smoke condensate (CSC) or chewing tobacco in the presence of ethanol was investigated using the 32P-postlabeling procedure. Concomitant treatment of the cells with ethanol increased the relative adduct level over that found in cells treated with tobacco smoke condensate only. Treatment with chewing tobacco resulted in slightly higher adduct levels than in controls. Treatment of the cells with ethanol did not significantly increase the uptake of a polycyclic aromatic hydrocarbon, benzo[j]fluoranthene, however, high tar CSC alone or in combination with ethanol significantly increased the uptake of radiolabeled benzo[j]fluoranthene, suggesting that increased uptake of the carcinogens may be one of the synergistic mechanisms of alcohol in oral carcinogenesis.

Determination of exposure to aflatoxins among Danish workers in animal-feed production through the analysis of aflatoxin B1 adducts to serum albumin.

Aflatoxin B1 is suspected as an etiologic factor in the increased risk for primary liver cancer among workers in animal-feed processing plants in Denmark. Aflatoxin bound to serum albumin was therefore measured for feed-processing workers. Blood samples were collected immediately after vacation and after four weeks of work, and aflatoxin was quantified by competitive enzyme-linked immunosorbant assay. Seven of 45 individuals with an estimated exposure of 64 ng aflatoxin B1.d-1.kg-1 body weight were positive. Three positive workers had been unloading a cargo with an aflatoxin B1 level of 26 micrograms.kg-1 raw material. The exposure level correlated well with the job titles. Dust samples collected at different sites showed considerable variation in the amount of aflatoxin B1 (nondetectable to 8 micrograms.kg-1 dust). The exposure to aflatoxin B1 may only partially explain the increased risk of liver cancer.

Metabolism of tobacco specific carcinogens in cultured rat buccal mucosa epithelial cells.

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.