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Toxicogenomics | Article Toxicogenomics | Article Genetic Variation in Genes Associated with Arsenic Metabolism: Glutathione S-Transferase Omega 1-1 and Purine Nucleoside Phosphorylase Polymorphisms in European and Indigenous Americans* Lizhi Yu,1 Kelly Kalla,1 Erin Guthrie,1 Amy Vidrine,1 and Walter T. Klimecki1,2 1Arizona Respiratory Center, Tucson, Arizona, USA; 2Southwest Environmental Sciences Center, Tucson, Arizona, USA between inorganic arsenic and organic Individual variability in human arsenic metabolism has been reported frequently in the litera- arsenic in the +V valence state, there is dif- ture. This variability could be an underlying determinant of individual susceptibility to arsenic- ferential cytotoxicity between inorganic induced disease in humans. Recent analysis revealing familial aggregation of arsenic metabolic arsenic in the +III valence state and inor- profiles suggests that genetic factors could underlie interindividual variation in arsenic metabo- ganic arsenic in the +V valence state. To lism. We screened two genes responsible for arsenic metabolism, human purine nucleoside phos- complicate matters further, more recently, phorylase (hNP), which functions as an arsenate reductase converting arsenate to arsenite, and it has been shown that, as opposed to the human glutathione S-transferase omega 1-1 (hGSTO1-1), which functions as a monomethylar- low potency of MMA(V) and DMA(V), sonic acid (MMA) reductase, converting MMA(V) to MMA(III), to develop a comprehensive MMA(III) and DMA(III) are potent induc- catalog of commonly occurring genetic polymorphisms in these genes. This catalog was gener- ers of apoptosis, cytosolic protein binding, ated by DNA sequencing of 22 individuals of European ancestry (EA) and 24 individuals of and epithelial hyperplasia (Thomas et al. indigenous American (IA) ancestry. In hNP, 48 polymorphic sites were observed, including 6 2001). In fact these methylated arsenic (III) that occurred in exons, of which 1 was nonsynonymous (G51S). One intronic polymorphism compounds may be the most potent toxi- occurred in a known enhancer region. In hGSTO1-1, 33 polymorphisms were observed. Six cants in the entire metabolic pathway. polymorphisms occurred in exons, of which 4 were nonsynonymous. In contrast to hNP, in Although no direct link exists between which the IA group was more polymorphic than the EA group, in hGSTO1-1 the EA group was arsenic-induced cytotoxicity and arsenic- more polymorphic than the IA group, which had only 1 polymorphism with a frequency > 10%. induced carcinogenesis, the differential bio- Populations representing genetic admixture between the EA and IA groups, such as Mexican logical activity of arsenic metabolites is Hispanics, could vary in the extent of polymorphism in these genes based upon the extent of probably not restricted to cytotoxicity. admixture. These data provide a framework in which to conduct genetic association studies of Thus, understanding arsenic metabolism is these two genes in relevant populations, thereby allowing hNP and hGSTO1-1 to be evaluated as likely to be key to a complete understand- potential susceptibility genes in human arsenicism. Key words: arsenic, biotransformation, ing of arsenic carcinogenesis. European ancestry, indigenous American ancestry, hGSTO1-1, hNP, polymorphisms, SNP. A second, equally compelling reason to Environ Health Perspect 111:1421–1427 (2003). doi:10.1289/txg.6420 available via explore arsenic metabolism is the evidence http://dx.doi.org/ [Online 21 July 2003] that the metabolism of arsenic may be genetically influenced, with significant interindividual variation in arsenic metabo- Arsenic-induced human carcinogenesis Toxicologists have been able to assemble lism among humans. Interspecies compar- remains one of the most perplexing mecha- the key steps of the arsenic biotransformation isons also suggest a genetic component to nistic puzzles in contemporary toxicology. pathway by identifying the chemical species arsenic metabolism. Comparison of nine Although current animal models of arsenic- of biotransformed arsenic. This pathway different strains of rats in which liver S9 induced carcinogenesis are of equivocal bio- includes several oxidation state changes, fractions were exposed to inorganic arsenic logical relevance, convincing human successive oxidative methylations, and at revealed a 2-fold difference between the epidemiologic data have identified the skin, least four metabolites (Vahter 2002). strain with the lowest rate of arsenic lung, and bladder as targets of carcinogene- Notwithstanding the lack of specifically methylation versus the strain with the sis caused by chronic exposure to arsenic identified carcinogenic mechanisms of highest rate (Thomas et al. 2001). Parallel (Bates et al. 1992). Several potential action, available evidence suggests that experiments corroborated the S9 fraction carcinogenic mechanisms have been pro- arsenic biotransformation is likely to be key results with intact hepatocytes from the posed, including inhibition of DNA repair to arsenic-induced disease. First, experi- nine strains. In experiments examining the enzymes, tumor promoter-like induction of mental evidence suggests that arsenic rate of formation of methylated arsenic in proliferation, alteration of DNA methyla- metabolism in humans could produce toxic hepatocytes taken from different human tion, and clastogenesis (Kitchin 2001). intermediates and certainly governs the in Notwithstanding their lack of in vivo vivo balance between chemical arsenic Address correspondence to W.T. Klimecki, Arizona potency in carcinogenesis assays, arsenic species with high biological potency Health Sciences Center, BRL-Room C112, 1609 compounds are potent toxicants both in and those with low biological potency. N. Warren Ave., Tucson, AZ 85724 USA. vitro and in vivo. Biological effects of in Historically, methylation of arsenic has Telephone: (520) 626-7470. Fax: (520) 626-5956. E-mail: [email protected] vitro or in vivo exposure to arsenic include been regarded as a detoxification mecha- *The online version of this article (available at apoptosis, protein ubiquitination, cellular nism (Abernathy et al. 1999). Within that http://www.ehponline.org) contains Supplemental proliferation, oxidative stress, and enzyme historical context, detoxification typically Material. inactivation (Asmuss et al. 2000; Chen et referred to the lower cytotoxic potency of This work was supported by National Institute al. 2001; Hunter 2000; Kirkpatrick et al. methylated arsenicals, namely monomethyl- for Environmental Health Sciences grant ES06694. 2003). Thus, arsenicals are clearly biologi- arsonic acid of valence V [MMA(V)] and WTK was also supported by National Heart, Lung, and Blood Institute grants HL66801, HL66806, cally active, but no definitive relationship dimethylarsinic acid of valence V [DMA(V)], and HL67672. has been established that links carcinogene- compared with inorganic arsenic species. In The authors declare they have no conflict of interest. sis to specific toxic endpoints. addition to the differential cytotoxicity Received 21 April 2003; accepted 14 July 2003. Environmental Health Perspectives • VOLUME 111 | NUMBER 11 | August 2003 1421 Toxicogenomics | Yu et al. donors, nearly a 10-fold difference was d’Etude du Polymorphism Humain sam- this visual inspection-confirmation was that observed (Styblo et al. 1999). Although ples. The geographical origin of the IA the polymorphism must be observed in this difference could be due to conditions samples consisted of 5 samples from Peru, multiple chromatograms from singleton surrounding donor organ condition or 9 samples from Mexico, 1 sample from polymorphisms (polymorphisms occurring assay conditions, it is interesting to note Ecuador, and 9 samples from Brazil. One in only one subject) or in multiple subjects. that a comparison of several large studies DNA sample isolated from chimpanzee For these confirmed polymorphic sites, measuring the distribution of urinary was also included in the study. These sam- each genotype for each subject was also arsenic metabolites in humans exposed to ples are commercially available; individual confirmed by visual inspection of chro- inorganic arsenic via drinking water sample identification and ordering infor- matograms. Polymorphic sites and associ- demonstrated a nearly 7-fold difference in mation are shown in the Supplemental ated subject-identified genotypes were the fraction of urinary arsenic as MMA Material, Table 1. automatically output to a relational data- (Vahter 2000). It is likely that some of this base for further analysis, which included variability is environmental; however, it is Polymerase Chain Reaction the automated generation of ethnicity- possible that genetic variation may underlie Genomic sequences for hNP and specific genotype frequencies, allele fre- some of the variation in arsenic metabo- hGSTO1-1 were accessed from the quencies, and goodness-of-fit tests for lism. A role for genetic determinants of UCSC Genome Browser (http://www. Hardy-Weinberg equilibrium. Haplotypes arsenic biotransformation is supported in genome.ucsc.edu) November 2002 freeze. were inferred using a Gibbs-sampling algo- recent work by Chung et al. (2002), in Polymerase chain reaction (PCR) ampli- rithm as implemented in the Phase soft- which familial aggregation in the pattern of cons were designed to completely traverse ware program (Stephens et al. 2001). urinary methylated arsenic metabolites was each gene, such that each amplicon was Because the accuracy
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