Skip to main content
NCBI home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2003 Aug;111(11):1421–1427. doi: 10.1289/ehp.6420

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, Walter T Klimecki 1
PMCID: PMC1241635  PMID: 12928150

Abstract

Individual variability in human arsenic metabolism has been reported frequently in the literature. This variability could be an underlying determinant of individual susceptibility to arsenic-induced disease in humans. Recent analysis revealing familial aggregation of arsenic metabolic profiles suggests that genetic factors could underlie interindividual variation in arsenic metabolism. We screened two genes responsible for arsenic metabolism, human purine nucleoside phosphorylase (hNP), which functions as an arsenate reductase converting arsenate to arsenite, and human glutathione S-transferase omega 1-1 (hGSTO1-1), which functions as a monomethylarsonic acid (MMA) reductase, converting MMA(V) to MMA(III), to develop a comprehensive catalog of commonly occurring genetic polymorphisms in these genes. This catalog was generated by DNA sequencing of 22 individuals of European ancestry (EA) and 24 individuals of indigenous American (IA) ancestry. In (Italic)hNP(/Italic), 48 polymorphic sites were observed, including 6 that occurred in exons, of which 1 was nonsynonymous (G51S). One intronic polymorphism occurred in a known enhancer region. In hGSTO1-1, 33 polymorphisms were observed. Six polymorphisms occurred in exons, of which 4 were nonsynonymous. In contrast to hNP, in which the IA group was more polymorphic than the EA group, in hGSTO1-1 the EA group was more polymorphic than the IA group, which had only 1 polymorphism with a frequency > 10%. Populations representing genetic admixture between the EA and IA groups, such as Mexican Hispanics, could vary in the extent of polymorphism in these genes based upon the extent of admixture. These data provide a framework in which to conduct genetic association studies of these two genes in relevant populations, thereby allowing hNP and hGSTO1-1 to be evaluated as potential susceptibility genes in human arsenicism.

Full Text

The Full Text of this article is available as a PDF (145.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abernathy C. O., Liu Y. P., Longfellow D., Aposhian H. V., Beck B., Fowler B., Goyer R., Menzer R., Rossman T., Thompson C. Arsenic: health effects, mechanisms of actions, and research issues. Environ Health Perspect. 1999 Jul;107(7):593–597. doi: 10.1289/ehp.99107593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Asmuss M., Mullenders L. H., Hartwig A. Interference by toxic metal compounds with isolated zinc finger DNA repair proteins. Toxicol Lett. 2000 Mar 15;112-113:227–231. doi: 10.1016/s0378-4274(99)00273-8. [DOI] [PubMed] [Google Scholar]
  3. Bates M. N., Smith A. H., Hopenhayn-Rich C. Arsenic ingestion and internal cancers: a review. Am J Epidemiol. 1992 Mar 1;135(5):462–476. doi: 10.1093/oxfordjournals.aje.a116313. [DOI] [PubMed] [Google Scholar]
  4. Board P. G., Coggan M., Chelvanayagam G., Easteal S., Jermiin L. S., Schulte G. K., Danley D. E., Hoth L. R., Griffor M. C., Kamath A. V. Identification, characterization, and crystal structure of the Omega class glutathione transferases. J Biol Chem. 2000 Aug 11;275(32):24798–24806. doi: 10.1074/jbc.M001706200. [DOI] [PubMed] [Google Scholar]
  5. Cerda-Flores Ricardo M., Villalobos-Torres Maria C., Barrera-Saldaña Hugo A., Cortés-Prieto Lizette M., Barajas Leticia O., Rivas Fernando, Carracedo Angel, Zhong Yixi, Barton Sara A., Chakraborty Ranajit. Genetic admixture in three Mexican Mestizo populations based on D1S80 and HLA-DQA1 loci. Am J Hum Biol. 2002 Mar-Apr;14(2):257–263. doi: 10.1002/ajhb.10020. [DOI] [PubMed] [Google Scholar]
  6. Chen F., Vallyathan V., Castranova V., Shi X. Cell apoptosis induced by carcinogenic metals. Mol Cell Biochem. 2001 Jun;222(1-2):183–188. [PubMed] [Google Scholar]
  7. Chung Joyce S., Kalman David A., Moore Lee E., Kosnett Michael J., Arroyo Alex P., Beeris Martin, Mazumder D. N. Guha, Hernandez Alexandra L., Smith Allan H. Family correlations of arsenic methylation patterns in children and parents exposed to high concentrations of arsenic in drinking water. Environ Health Perspect. 2002 Jul;110(7):729–733. doi: 10.1289/ehp.02110729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Devlin B., Risch N. A comparison of linkage disequilibrium measures for fine-scale mapping. Genomics. 1995 Sep 20;29(2):311–322. doi: 10.1006/geno.1995.9003. [DOI] [PubMed] [Google Scholar]
  9. Ewing B., Hillier L., Wendl M. C., Green P. Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res. 1998 Mar;8(3):175–185. doi: 10.1101/gr.8.3.175. [DOI] [PubMed] [Google Scholar]
  10. Gordon D., Abajian C., Green P. Consed: a graphical tool for sequence finishing. Genome Res. 1998 Mar;8(3):195–202. doi: 10.1101/gr.8.3.195. [DOI] [PubMed] [Google Scholar]
  11. Hunter E. S., 3rd Role of oxidative damage in arsenic-induced teratogenesis. Teratology. 2000 Oct;62(4):240–240. doi: 10.1002/1096-9926(200010)62:4<240::AID-TERA14>3.0.CO;2-8. [DOI] [PubMed] [Google Scholar]
  12. Jonsson J. J., Converse A., McIvor R. S. An enhancer in the first intron of the human purine nucleoside phosphorylase-encoding gene. Gene. 1994 Mar 25;140(2):187–193. doi: 10.1016/0378-1119(94)90543-6. [DOI] [PubMed] [Google Scholar]
  13. Jonsson J. J., Foresman M. D., Wilson N., McIvor R. S. Intron requirement for expression of the human purine nucleoside phosphorylase gene. Nucleic Acids Res. 1992 Jun 25;20(12):3191–3198. doi: 10.1093/nar/20.12.3191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jonsson J. J., Williams S. R., McIvor R. S. Sequence and functional characterization of the human purine nucleoside phosphorylase promoter. Nucleic Acids Res. 1991 Sep 25;19(18):5015–5020. doi: 10.1093/nar/19.18.5015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kirkpatrick D. S., Dale K. V., Catania J. M., Gandolfi A. J. Low-level arsenite causes accumulation of ubiquitinated proteins in rabbit renal cortical slices and HEK293 cells. Toxicol Appl Pharmacol. 2003 Jan 15;186(2):101–109. doi: 10.1016/s0041-008x(02)00019-4. [DOI] [PubMed] [Google Scholar]
  16. Kitchin K. T. Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. Toxicol Appl Pharmacol. 2001 May 1;172(3):249–261. doi: 10.1006/taap.2001.9157. [DOI] [PubMed] [Google Scholar]
  17. Kong Augustine, Gudbjartsson Daniel F., Sainz Jesus, Jonsdottir Gudrun M., Gudjonsson Sigurjon A., Richardsson Bjorgvin, Sigurdardottir Sigrun, Barnard John, Hallbeck Bjorn, Masson Gisli. A high-resolution recombination map of the human genome. Nat Genet. 2002 Jun 10;31(3):241–247. doi: 10.1038/ng917. [DOI] [PubMed] [Google Scholar]
  18. Laliberte Ronald E., Perregaux David G., Hoth Lise R., Rosner Philip J., Jordan Crystal K., Peese Kevin M., Eggler James F., Dombroski Mark A., Geoghegan Kieran F., Gabel Christopher A. Glutathione s-transferase omega 1-1 is a target of cytokine release inhibitory drugs and may be responsible for their effect on interleukin-1beta posttranslational processing. J Biol Chem. 2003 Mar 6;278(19):16567–16578. doi: 10.1074/jbc.M211596200. [DOI] [PubMed] [Google Scholar]
  19. Markert M. L. Purine nucleoside phosphorylase deficiency. Immunodefic Rev. 1991;3(1):45–81. [PubMed] [Google Scholar]
  20. Nickerson D. A., Tobe V. O., Taylor S. L. PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res. 1997 Jul 15;25(14):2745–2751. doi: 10.1093/nar/25.14.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Radabaugh Timothy R., Sampayo-Reyes Adriana, Zakharyan Robert A., Aposhian H. Vasken. Arsenate reductase II. Purine nucleoside phosphorylase in the presence of dihydrolipoic acid is a route for reduction of arsenate to arsenite in mammalian systems. Chem Res Toxicol. 2002 May;15(5):692–698. doi: 10.1021/tx0101853. [DOI] [PubMed] [Google Scholar]
  22. Rutherford K., Parkhill J., Crook J., Horsnell T., Rice P., Rajandream M. A., Barrell B. Artemis: sequence visualization and annotation. Bioinformatics. 2000 Oct;16(10):944–945. doi: 10.1093/bioinformatics/16.10.944. [DOI] [PubMed] [Google Scholar]
  23. Sato T., Wakabayashi Y. [PNP deficiency]. Ryoikibetsu Shokogun Shirizu. 1998;(21 Pt 2):228–231. [PubMed] [Google Scholar]
  24. Stephens M., Smith N. J., Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001 Mar 9;68(4):978–989. doi: 10.1086/319501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Styblo M., Del Razo L. M., LeCluyse E. L., Hamilton G. A., Wang C., Cullen W. R., Thomas D. J. Metabolism of arsenic in primary cultures of human and rat hepatocytes. Chem Res Toxicol. 1999 Jul;12(7):560–565. doi: 10.1021/tx990050l. [DOI] [PubMed] [Google Scholar]
  26. Tanaka-Kagawa Toshiko, Jinno Hideto, Hasegawa Tatsuya, Makino Yuko, Seko Yoshiyuki, Hanioka Nobumitsu, Ando Masanori. Functional characterization of two variant human GSTO 1-1s (Ala140Asp and Thr217Asn). Biochem Biophys Res Commun. 2003 Feb 7;301(2):516–520. doi: 10.1016/s0006-291x(02)03066-8. [DOI] [PubMed] [Google Scholar]
  27. Thomas D. J., Styblo M., Lin S. The cellular metabolism and systemic toxicity of arsenic. Toxicol Appl Pharmacol. 2001 Oct 15;176(2):127–144. doi: 10.1006/taap.2001.9258. [DOI] [PubMed] [Google Scholar]
  28. Tishkoff S. A., Pakstis A. J., Ruano G., Kidd K. K. The accuracy of statistical methods for estimation of haplotype frequencies: an example from the CD4 locus. Am J Hum Genet. 2000 Jun 19;67(2):518–522. doi: 10.1086/303000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Vahter M., Couch R., Nermell B., Nilsson R. Lack of methylation of inorganic arsenic in the chimpanzee. Toxicol Appl Pharmacol. 1995 Aug;133(2):262–268. doi: 10.1006/taap.1995.1150. [DOI] [PubMed] [Google Scholar]
  30. Vahter M. Methylation of inorganic arsenic in different mammalian species and population groups. Sci Prog. 1999;82(Pt 1):69–88. doi: 10.1177/003685049908200104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Whitbread Astrid K., Tetlow Natasha, Eyre Helen J., Sutherland Grant R., Board Philip G. Characterization of the human Omega class glutathione transferase genes and associated polymorphisms. Pharmacogenetics. 2003 Mar;13(3):131–144. doi: 10.1097/00008571-200303000-00003. [DOI] [PubMed] [Google Scholar]
  32. Wildfang E., Radabaugh T. R., Vasken Aposhian H. Enzymatic methylation of arsenic compounds. IX. Liver arsenite methyltransferase and arsenate reductase activities in primates. Toxicology. 2001 Nov 30;168(3):213–221. doi: 10.1016/s0300-483x(01)00481-4. [DOI] [PubMed] [Google Scholar]
  33. Yin Z. L., Dahlstrom J. E., Le Couteur D. G., Board P. G. Immunohistochemistry of omega class glutathione S-transferase in human tissues. J Histochem Cytochem. 2001 Aug;49(8):983–987. doi: 10.1177/002215540104900806. [DOI] [PubMed] [Google Scholar]
  34. Zakharyan R. A., Sampayo-Reyes A., Healy S. M., Tsaprailis G., Board P. G., Liebler D. C., Aposhian H. V. Human monomethylarsonic acid (MMA(V)) reductase is a member of the glutathione-S-transferase superfamily. Chem Res Toxicol. 2001 Aug;14(8):1051–1057. doi: 10.1021/tx010052h. [DOI] [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES