CYP1A1, GSTM1, and GSTP1 Genetic Polymorphisms and Urinary 1-Hydroxypyrene Excretion in Non-Occupationally Exposed Individuals 1 Pratibha V. Nerurkar, Leila Okinaka, Chris Aoki, Ann Seifried, Annette Lum-Jones, Lynne R. Wilkens, and Loı ¨c Le Marchand 2 Cancer Research Center of Hawaii, Etiology Program, University of Hawaii, Honolulu, Hawaii 96813 Abstract The CYP1A1 and glutathione S-transferase enzymes (e.g., GSTM1 and GSTP1) are involved in the activation and conjugation of polycyclic aromatic hydrocarbons (PAHs), respectively, and are controlled by genes that are polymorphic. The CYP1A1*2 allelic variant has been associated with elevated urinary 1-hydroxypyrene (1- OHP), a proposed marker for internal dose of activated PAHs, in coke-oven workers. We investigated whether this association could be observed at low exposure levels, such as those experienced by the general population. We conducted a cross-sectional study among 188 individuals (106 Japanese, 60 Caucasians, and 22 Hawaiians) who were selected as controls in a population-based case- control study and provided lifestyle information, a 12-h urine specimen, and a blood sample. 1-OHP was analyzed by high-performance liquid chromatography after enzymatic hydrolysis. Lymphocyte DNA was used for PCR-based genotyping. Smokers excreted twice as much 1-OHP (geometric mean, 0.51 nmol/12 h) as nonsmokers (geometric mean, 0.27 nmol/12 h; P  0.006). Overall and among nonsmokers, 1-OHP urinary levels did not differ by CYP1A1, GSTM1, or GSTP1 genotypes. However, after adjusting for age, ethnicity, and number of cigarettes per day, smokers with at least one CYP1A1*2 variant allele excreted 2.0-fold more 1-OHP than smokers with the wild-type genotype (P  0.02). Similar results were obtained for the CYP1A1*3 variant allele. The present data add to the growing evidence suggesting that individuals with the (linked) CYP1A1*2 or *3 variant alleles have a greater capacity to activate PAHs from tobacco smoke and occupational exposure and, as a result, are at greater risk for PAH-related cancers, especially certain respiratory cancers. Introduction PAHs 3 are generated by the incomplete combustion of organic materials. The general population is exposed to low levels of these chemicals, mostly through smoking and diet (1, 2). PAHs undergo metabolic activation, mainly by cytochrome P4501A1 (3), to diol epoxides capable of binding covalently to DNA, potentially initiating the carcinogenic process. Activated PAH metabolites can be detoxified by phase II enzymes, such as GST and uridine diphosphoglucuronosyltransferase, which cat- alyze conjugative reactions of oxidative products (4, 5). 1-OHP, a major oxidative metabolite of pyrene that can be measured in urine, is commonly used as a biomarker of internal dose for PAHs (6). Increased urinary levels of 1-OHP have been ob- served after ingestion of broiled meats or application of coal tar-based ointment, as well as among smokers and workers exposed to coal tar fumes, mineral oil, or bitumen (7–10). When 1-OHP is measured after treating the urine with decon- jugating enzymes (e.g., -glucuronidase), the sum of conju- gated and deconjugated species are quantified, reflecting the total amount of hydroxylated metabolite. Although 1-OHP it- self is not a carcinogen, it can be used as a marker for a major activating step in the metabolism of PAHs. Past studies have indicated that there is wide variability in urinary 1-OHP excre- tion among similarly exposed individuals, suggesting interin- dividual variability in PAH activation (7, 11, 12). The CYP1A1 gene is polymorphically expressed in hu- mans, and variant alleles at this locus have been associated with an increased risk for lung cancer in smokers (13–15). In a population-based case-control study, we have shown recently that the presence of the CYP1A1*2 variant allele was associated with a 2.4-fold (95% CI, 1.2– 4.7) increased risk of squamous cell carcinoma of the lung, a tumor thought to be specifically related to PAHs (15). A number of in vitro studies have sug- gested that individuals with the CYP1A1*2 or the closely linked CYP1A1*3 variant allele may have a greater capacity to activate PAHs (16). However, few in vivo confirmatory data are avail- able. Two recent occupational epidemiology studies have ex- plored the association between CYP1A1 and urinary 1-OHP among workers exposed to relatively high levels of PAHs (17, 18). Both found higher postshift 1-OHP levels for individuals with the variant CYP1A1*2 allele, compared with those with the common allele (17, 18). The present study investigated whether the same association could be observed in the general population, which is typically exposed to only low levels of PAHs. Received 3/16/00; revised 8/9/00; accepted 8/14/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported in part by Grants 5 R01 CA 60987 and 1 R01 CA 72520 from the NIH. 2 To whom requests for reprints should be addressed, at Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, 1236 Lauhala Street, Suite 407, Honolulu, Hawaii 96813. 3 The abbreviations used are: PAH, polycyclic aromatic hydrocarbon; GST, glutathione S-transferase; 1-OHP, 1-hydroxypyrene; CI, confidence interval; HPLC, high-performance liquid chromatography. 1119 Vol. 9, 1119 –1122, October 2000 Cancer Epidemiology, Biomarkers & Prevention Research. on December 14, 2021. © 2000 American Association for Cancer cebp.aacrjournals.org Downloaded from