Polycyclic aromatic hydrocarbons (PAH) are a well established class of environmental carcinogens which are likely to play a significant role as causative agents for cancer in cigarette smokers and in occupationally exposed workers. Benzo[a]pvrene (BaP), a potent locally acting carcinogen, is a prototypical PAH. BaP requires metabolic activation by host enzymes to exert its carcinogenic effects, and there are competing detoxification reactions, which are protective and facilitate excretion. Many studies have shown that there are wide interindividual differences in human metabolic activation of BaP. Individuals who metabolically activate BaP extensively will have higher levels of DNA adducts formed by way of its major ultimate carcinogen, (7R,85)-dihydroxy-(9S.10R)cpoxv-7.S,9.lO-tetrahydrobenzo[a]pyrene [(+/-i-anti-BPDE] than those who readily detoxify BaP. These individuals are believed to he at higher risk for cancer. A currently popular approach toward identifying such individuals is identification of polymorphisms in genes coding for enzymes involved in BaP and PAH metabolism. Many epidemiologic studies have investigated the relationship between polymorphisms in these genes and cancer. The results of these studies have been generally equivocal. Because of the complexity of PAH metabolism, it unlikely that a variant in a single gene will predict overall extents of metabolic activation. For example, some genes such as C}'PIAI are involved in both the metabolic activation and detoxification of PAH. Few studies have actually investigated the relationship between genetic polymorphisms and PAH metabolism in humans. In this project, we propose to integrate genotyping ping data with PAH metabolite profiles and DNA adduct levels in humans. Our goal is to develop a practical method or assessing individual differences in human PAH metabolic activation and detoxification. Our hypothesis is that PAH metabolite phenotyping will predict DNA adduct levels. The specific aims are: 1) Develop methods to quantify the following metabolites of BaP in human urine: 7.8,9, I 0-tetrahydroxy-7,8.9. lO-tetrahydrobenzo[a]pyrene [BaP-tetraols], hvdroxyBaPs, BaP-diols, and N-acetylecysteine conjugates of BPDE, 2) Determine the relationship between these metabolite levels and gene polymorphisms in smokers, examining cytochrome P450 lAl [CYP/Al], CYPIB], microsomal epoxide hydrolase [EPHXI], glutathione transferase M1 [CSTM1], and GSTPI; 3) Determine the relationship of urinary BaP activation:detoxification metabolite ratios and genotyping data to BPDE-DNA adduct levels in human peripheral blood lymphocytes and lung; and 4) determine the relationship of urinary BaP activation:detoxification ratios to the ratios of similar metabolites of phenanthrene. The results of this proposal will provide critical information directly relevant to determining interindividual differences in PAH metabolism, which can ultimately be used in a rigorous test of the hypothesis that such differences affect cancer incidence in smokers.
NIH ExPorter
NIH ExPorter