Beyond detoxification: Pleiotropic functions of multiple glutathione S-transferase isoforms protect mice against a toxic electrophile
Autoři:
Kelsey A. Behrens aff001; Leigh A. Jania aff002; John N. Snouwaert aff002; MyTrang Nguyen aff002; Sheryl S. Moy aff003; Andrey P. Tikunov aff004; Jeffrey M. Macdonald aff004; Beverly H. Koller aff001
Působiště autorů:
Curriculum in Toxicology & Environmental Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
aff001; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
aff002; Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
aff003; Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
aff004
Vyšlo v časopise:
PLoS ONE 14(11)
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pone.0225449
Souhrn
Environmental and endogenous electrophiles cause tissue damage through their high reactivity with endogenous nucleophiles such as DNA, proteins, and lipids. Protection against damage is mediated by glutathione (GSH) conjugation, which can occur spontaneously or be facilitated by the glutathione S-transferase (GST) enzymes. To determine the role of GST enzymes in protection against electrophiles as well as the role of specific GST families in mediating this protection, we exposed mutant mouse lines lacking the GSTP, GSTM, and/or GSTT enzyme families to the model electrophile acrylamide, a ubiquitous dietary contaminant known to cause adverse effects in humans. An analysis of urinary metabolites after acute acrylamide exposure identified the GSTM family as the primary mediator of GSH conjugation to acrylamide. However, surprisingly, mice lacking only this enzyme family did not show increased toxicity after an acute acrylamide exposure. Therefore, GSH conjugation is not the sole mechanism by which GSTs protect against the toxicity of this substrate. Given the prevalence of null GST polymorphisms in the human population (approximately 50% for GSTM1 and 20–50% for GSTT1), a substantial portion of the population may also have impaired acrylamide metabolism. However, our study also defines a role for GSTP and/or GSTT in protection against acrylamide mediated toxicity. Thus, while the canonical detoxification function of GSTs may be impaired in GSTM null individuals, disease risk secondary to acrylamide exposure may be mitigated through non-canonical pathways involving members of the GSTP and/or GSTT families.
Klíčová slova:
Enzymes – White blood cells – Spleen – Toxicity – Urine – Enzyme metabolism – Stomach – Glutathione chromatography
Zdroje
1. Sheehan D, Meade G, Foley VM, Dowd CA. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. The Biochemical journal. 2001;360(Pt 1):1–16. Epub 2001/11/07. doi: 10.1042/0264-6021:3600001 11695986; PubMed Central PMCID: PMC1222196.
2. Hayes JD, Strange RC. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000;61(3):154–66. Epub 2000/09/06. doi: 10.1159/000028396 10971201.
3. McIlwain CC, Townsend DM, Tew KD. Glutathione S-transferase polymorphisms: cancer incidence and therapy. Oncogene. 2006;25(11):1639–48. Epub 2006/03/22. doi: 10.1038/sj.onc.1209373 16550164; PubMed Central PMCID: PMC6361140.
4. Chang J, Ma JZ, Zeng Q, Cechova S, Gantz A, Nievergelt C, et al. Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK). American journal of physiology Renal physiology. 2013;304(4):F348–55. Epub 2012/12/12. doi: 10.1152/ajprenal.00568.2012 23220723; PubMed Central PMCID: PMC3566499.
5. Josephy PD. Genetic variations in human glutathione transferase enzymes: significance for pharmacology and toxicology. Human genomics and proteomics: HGP. 2010;2010:876940. Epub 2010/10/29. doi: 10.4061/2010/876940 20981235; PubMed Central PMCID: PMC2958679.
6. Henderson CJ, Wolf CR. Knockout and transgenic mice in glutathione transferase research. Drug metabolism reviews. 2011;43(2):152–64. Epub 2011/03/24. doi: 10.3109/03602532.2011.562900 21425933.
7. Ginsberg G, Smolenski S, Hattis D, Guyton KZ, Johns DO, Sonawane B. Genetic Polymorphism in Glutathione Transferases (GST): Population distribution of GSTM1, T1, and P1 conjugating activity. Journal of toxicology and environmental health Part B, Critical reviews. 2009;12(5–6):389–439. Epub 2010/02/26. doi: 10.1080/10937400903158375 20183528.
8. Engle MR, Singh SP, Czernik PJ, Gaddy D, Montague DC, Ceci JD, et al. Physiological role of mGSTA4-4, a glutathione S-transferase metabolizing 4-hydroxynonenal: generation and analysis of mGsta4 null mouse. Toxicology and applied pharmacology. 2004;194(3):296–308. Epub 2004/02/06. doi: 10.1016/j.taap.2003.10.001 14761685.
9. Henderson CJ, Wolf CR, Kitteringham N, Powell H, Otto D, Park BK. Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(23):12741–5. Epub 2000/11/01. doi: 10.1073/pnas.220176997 11058152; PubMed Central PMCID: PMC18834.
10. McMillan DH, van der Velden JL, Lahue KG, Qian X, Schneider RW, Iberg MS, et al. Attenuation of lung fibrosis in mice with a clinically relevant inhibitor of glutathione-S-transferase pi. JCI insight. 2016;1(8). Epub 2016/07/01. doi: 10.1172/jci.insight.85717 27358914; PubMed Central PMCID: PMC4922427.
11. Oakley AJ, Lo Bello M, Nuccetelli M, Mazzetti AP, Parker MW. The ligandin (non-substrate) binding site of human Pi class glutathione transferase is located in the electrophile binding site (H-site). Journal of molecular biology. 1999;291(4):913–26. Epub 1999/08/24. doi: 10.1006/jmbi.1999.3029 10452896.
12. Townsend DM, Manevich Y, He L, Hutchens S, Pazoles CJ, Tew KD. Novel role for glutathione S-transferase pi. Regulator of protein S-Glutathionylation following oxidative and nitrosative stress. The Journal of biological chemistry. 2009;284(1):436–45. Epub 2008/11/08. doi: 10.1074/jbc.M805586200 18990698; PubMed Central PMCID: PMC2610519.
13. Zhang J, Grek C, Ye ZW, Manevich Y, Tew KD, Townsend DM. Pleiotropic functions of glutathione S-transferase P. Advances in cancer research. 2014;122:143–75. Epub 2014/06/30. doi: 10.1016/B978-0-12-420117-0.00004-9 24974181; PubMed Central PMCID: PMC5079281.
14. Tew KD, Manevich Y, Grek C, Xiong Y, Uys J, Townsend DM. The role of glutathione S-transferase P in signaling pathways and S-glutathionylation in cancer. Free radical biology & medicine. 2011;51(2):299–313. Epub 2011/05/12. doi: 10.1016/j.freeradbiomed.2011.04.013 21558000; PubMed Central PMCID: PMC3125017.
15. Jones JT, Qian X, van der Velden JL, Chia SB, McMillan DH, Flemer S, et al. Glutathione S-transferase pi modulates NF-kappaB activation and pro-inflammatory responses in lung epithelial cells. Redox biology. 2016;8:375–82. Epub 2016/04/09. doi: 10.1016/j.redox.2016.03.005 27058114; PubMed Central PMCID: PMC4827796.
16. Xiang Z, Snouwaert JN, Kovarova M, Nguyen M, Repenning PW, Latour AM, et al. Mice lacking three Loci encoding 14 glutathione transferase genes: a novel tool for assigning function to the GSTP, GSTM, and GSTT families. Drug metabolism and disposition: the biological fate of chemicals. 2014;42(6):1074–83. Epub 2014/03/25. doi: 10.1124/dmd.113.056481 24658454; PubMed Central PMCID: PMC4014662.
17. Calleman CJ, Wu Y, He F, Tian G, Bergmark E, Zhang S, et al. Relationships between biomarkers of exposure and neurological effects in a group of workers exposed to acrylamide. Toxicology and applied pharmacology. 1994;126(2):361–71. Epub 1994/06/01. doi: 10.1006/taap.1994.1127 8209389.
18. Tareke E, Rydberg P, Karlsson P, Eriksson S, Tornqvist M. Analysis of acrylamide, a carcinogen formed in heated foodstuffs. Journal of agricultural and food chemistry. 2002;50(17):4998–5006. Epub 2002/08/09. doi: 10.1021/jf020302f 12166997.
19. Organization WH. Health implications of acrylamide in food. 2002.
20. Lineback DR, Coughlin JR, Stadler RH. Acrylamide in foods: a review of the science and future considerations. Annual review of food science and technology. 2012;3:15–35. Epub 2011/12/06. doi: 10.1146/annurev-food-022811-101114 22136129.
21. Virk-Baker MK, Nagy TR, Barnes S, Groopman J. Dietary acrylamide and human cancer: a systematic review of literature. Nutrition and cancer. 2014;66(5):774–90. Epub 2014/05/31. doi: 10.1080/01635581.2014.916323 PubMed Central PMCID: PMC4164905. 24875401
22. Twaddle NC, Churchwell MI, McDaniel LP, Doerge DR. Autoclave sterilization produces acrylamide in rodent diets: implications for toxicity testing. Journal of agricultural and food chemistry. 2004;52(13):4344–9. Epub 2004/06/24. doi: 10.1021/jf0497657 15212490.
23. Sumner SCJ, MacNeela JP, Fennell TR. Characterization and quantitation of urinary metabolites of [1,2,3-13C]acrylamide in rats and mice using carbon-13 nuclear magnetic resonance spectroscopy. Chemical Research in Toxicology. 1992;5(1):81–9. doi: 10.1021/tx00025a014 1581543
24. Fennell TR, Sumner SC, Snyder RW, Burgess J, Friedman MA. Kinetics of elimination of urinary metabolites of acrylamide in humans. Toxicological sciences: an official journal of the Society of Toxicology. 2006;93(2):256–67. Epub 2006/07/28. doi: 10.1093/toxsci/kfl069 16870689.
25. Fennell TR, Sumner SC, Snyder RW, Burgess J, Spicer R, Bridson WE, et al. Metabolism and hemoglobin adduct formation of acrylamide in humans. Toxicological sciences: an official journal of the Society of Toxicology. 2005;85(1):447–59. Epub 2004/12/31. doi: 10.1093/toxsci/kfi069 15625188.
26. Knight TR, Choudhuri S, Klaassen CD. Constitutive mRNA expression of various glutathione S-transferase isoforms in different tissues of mice. Toxicological sciences: an official journal of the Society of Toxicology. 2007;100(2):513–24. Epub 2007/09/25. doi: 10.1093/toxsci/kfm233 17890767.
27. Hayes JD, Flanagan JU, Jowsey IR. Glutathione transferases. Annual review of pharmacology and toxicology. 2005;45:51–88. Epub 2005/04/12. doi: 10.1146/annurev.pharmtox.45.120403.095857 15822171.
28. Baars AJ, Jansen M, Breimer DD. The influence of phenobarbital, 3-methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin on glutathione S-transferase activity of rat liver cytosol. Biochemical pharmacology. 1978;27(21):2487–97. Epub 1978/01/01. doi: 10.1016/0006-2952(78)90314-3 728202.
29. Jemth P, Mannervik B. Kinetic characterization of recombinant human glutathione transferase T1-1, a polymorphic detoxication enzyme. Archives of biochemistry and biophysics. 1997;348(2):247–54. Epub 1998/01/22. doi: 10.1006/abbi.1997.0357 9434735.
30. Ghanayem BI, Witt KL, Kissling GE, Tice RR, Recio L. Absence of acrylamide-induced genotoxicity in CYP2E1-null mice: evidence consistent with a glycidamide-mediated effect. Mutation research. 2005;578(1–2):284–97. Epub 2005/06/29. doi: 10.1016/j.mrfmmm.2005.05.004 15982677.
31. Gamboa da Costa G, Churchwell MI, Hamilton LP, Von Tungeln LS, Beland FA, Marques MM, et al. DNA adduct formation from acrylamide via conversion to glycidamide in adult and neonatal mice. Chem Res Toxicol. 2003;16(10):1328–37. Epub 2003/10/21. doi: 10.1021/tx034108e 14565774.
32. Barber DS, Hunt JR, Ehrich MF, Lehning EJ, LoPachin RM. Metabolism, toxicokinetics and hemoglobin adduct formation in rats following subacute and subchronic acrylamide dosing. Neurotoxicology. 2001;22(3):341–53. Epub 2001/07/18. doi: 10.1016/s0161-813x(01)00024-9 11456335.
33. Brat DJ, Brimijoin S. Acrylamide and glycidamide impair neurite outgrowth in differentiating N1E.115 neuroblastoma without disturbing rapid bidirectional transport of organelles observed by video microscopy. Journal of neurochemistry. 1993;60(6):2145–52. Epub 1993/06/01. doi: 10.1111/j.1471-4159.1993.tb03499.x 8492122.
34. Costa LG, Deng H, Calleman CJ, Bergmark E. Evaluation of the neurotoxicity of glycidamide, an epoxide metabolite of acrylamide: behavioral, neurochemical and morphological studies. Toxicology. 1995;98(1–3):151–61. Epub 1995/04/12. doi: 10.1016/0300-483x(94)02986-5 7740544.
35. Gilbert SG, Maurissen JP. Assessment of the effects of acrylamide, methylmercury, and 2,5-hexanedione on motor functions in mice. Journal of toxicology and environmental health. 1982;10(1):31–41. Epub 1982/07/01. doi: 10.1080/15287398209530228 7131587.
36. Ko MH, Chen WP, Lin-Shiau SY, Hsieh ST. Age-dependent acrylamide neurotoxicity in mice: morphology, physiology, and function. Experimental neurology. 1999;158(1):37–46. Epub 1999/08/17. doi: 10.1006/exnr.1999.7102 10448416.
37. Von Burg R, Penney DP, Conroy PJ. Acrylamide neurotoxicity in the mouse: a behavioral, electrophysiological and morphological study. Journal of applied toxicology: JAT. 1981;1(4):227–33. Epub 1981/08/01. doi: 10.1002/jat.2550010409 7184942.
38. Shelby MD, Cain KT, Hughes LA, Braden PW, Generoso WM. Dominant lethal effects of acrylamide in male mice. Mutation research. 1986;173(1):35–40. Epub 1986/01/01. doi: 10.1016/0165-7992(86)90008-4 3941677.
39. Yoon E, Babar A, Choudhary M, Kutner M, Pyrsopoulos N. Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update. Journal of clinical and translational hepatology. 2016;4(2):131–42. Epub 2016/06/29. doi: 10.14218/JCTH.2015.00052 27350943; PubMed Central PMCID: PMC4913076.
40. Zaidi SI, Raisuddin S, Singh KP, Jafri A, Husain R, Husain MM, et al. Acrylamide induced immunosuppression in rats and its modulation by 6-MFA, an interferon inducer. Immunopharmacology and immunotoxicology. 1994;16(2):247–60. Epub 1994/05/01. doi: 10.3109/08923979409007093 8077609.
41. Doerge DR, Young JF, McDaniel LP, Twaddle NC, Churchwell MI. Toxicokinetics of acrylamide and glycidamide in B6C3F1 mice. Toxicology and applied pharmacology. 2005;202(3):258–67. Epub 2005/01/26. doi: 10.1016/j.taap.2004.07.001 15667831.
42. Sun J, Schnackenberg LK, Pence L, Bhattacharyya S, Doerge DR, Bowyer JF, et al. Metabolomic analysis of urine from rats chronically dosed with acrylamide using NMR and LC/MS. Metabolomics. 2010;6(4):550–63. doi: 10.1007/s11306-010-0225-8
43. Lethco EJ, Wallace WC. The metabolism of saccharin in animals. Toxicology. 1975;3(3):287–300. Epub 1975/01/01. doi: 10.1016/0300-483x(75)90030-x 1092032.
44. Byard JL, Goldberg L. The metabolism of saccharin in laboratory animals. Food and cosmetics toxicology. 1973;11(3):391–402. Epub 1973/06/01. doi: 10.1016/0015-6264(73)90005-9 4199497.
45. Testa B, Kramer SD. The biochemistry of drug metabolism—an introduction: part 4. reactions of conjugation and their enzymes. Chemistry & biodiversity. 2008;5(11):2171–336. Epub 2008/11/28. doi: 10.1002/cbdv.200890199 19035562.
46. Doerge DR, Twaddle NC, Boettcher MI, McDaniel LP, Angerer J. Urinary excretion of acrylamide and metabolites in Fischer 344 rats and B6C3F(1) mice administered a single dose of acrylamide. Toxicology letters. 2007;169(1):34–42. Epub 2007/01/17. doi: 10.1016/j.toxlet.2006.12.002 17224249.
47. Dixit R, Mukhtar H, Seth PK, Murti CR. Binding of acrylamide with glutathione-S-transferases. Chemico-biological interactions. 1980;32(3):353–9. Epub 1980/11/01. doi: 10.1016/0009-2797(80)90103-9 7428122.
48. Dixit R, Mukhtar H, Seth PK, Murti CR. Conjugation of acrylamide with glutathione catalysed by glutathione-S-transferases of rat liver and brain. Biochemical pharmacology. 1981;30(13):1739–44. Epub 1981/07/01. doi: 10.1016/0006-2952(81)90003-4 7271861.
49. Sumner SC, Williams CC, Snyder RW, Krol WL, Asgharian B, Fennell TR. Acrylamide: a comparison of metabolism and hemoglobin adducts in rodents following dermal, intraperitoneal, oral, or inhalation exposure. Toxicological sciences: an official journal of the Society of Toxicology. 2003;75(2):260–70. Epub 2003/07/29. doi: 10.1093/toxsci/kfg191 12883088.
50. Abel EL, Opp SM, Verlinde CL, Bammler TK, Eaton DL. Characterization of atrazine biotransformation by human and murine glutathione S-transferases. Toxicological sciences: an official journal of the Society of Toxicology. 2004;80(2):230–8. Epub 2004/04/30. doi: 10.1093/toxsci/kfh152 15115887.
51. Seidegard J, Vorachek WR, Pero RW, Pearson WR. Hereditary differences in the expression of the human glutathione transferase active on trans-stilbene oxide are due to a gene deletion. Proceedings of the National Academy of Sciences of the United States of America. 1988;85(19):7293–7. Epub 1988/10/01. doi: 10.1073/pnas.85.19.7293 3174634; PubMed Central PMCID: PMC282172.
52. Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, et al. Regulation of JNK signaling by GSTp. The EMBO journal. 1999;18(5):1321–34. Epub 1999/03/04. doi: 10.1093/emboj/18.5.1321 10064598; PubMed Central PMCID: PMC1171222.
53. Zhang J, Ye ZW, Singh S, Townsend DM, Tew KD. An evolving understanding of the S-glutathionylation cycle in pathways of redox regulation. Free radical biology & medicine. 2018;120:204–16. Epub 2018/03/27. doi: 10.1016/j.freeradbiomed.2018.03.038 29578070; PubMed Central PMCID: PMC5940525.
54. Martyniuk CJ, Feswick A, Fang B, Koomen JM, Barber DS, Gavin T, et al. Protein targets of acrylamide adduct formation in cultured rat dopaminergic cells. Toxicology letters. 2013;219(3):279–87. Epub 2013/04/10. doi: 10.1016/j.toxlet.2013.03.031 23566896; PubMed Central PMCID: PMC3707521.
55. University of North Carolina at Chapel Hill Standard on Humane Endpoints in Rodents: UNC IACUC; 2017. Available from: https://research.unc.edu/files/2012/11/Guidelines-for-Humane-Endpoints-of-Rodents.pdf.
56. Habig WH, Pabst MJ, Jakoby WB. Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. The Journal of biological chemistry. 1974;249(22):7130–9. Epub 1974/11/25. 4436300.
57. Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, et al. Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environmental and molecular mutagenesis. 2000;35(3):206–21. Epub 2000/03/29. doi: 10.1002/(sici)1098-2280(2000)35:3<206::aid-em8>3.0.co;2-j 10737956.
58. Gyori BM, Venkatachalam G, Thiagarajan PS, Hsu D, Clement MV. OpenComet: an automated tool for comet assay image analysis. Redox biology. 2014;2:457–65. Epub 2014/03/14. doi: 10.1016/j.redox.2013.12.020 24624335; PubMed Central PMCID: PMC3949099.
Článok vyšiel v časopise
PLOS One
2019 Číslo 11
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- Nejasný stín na plicích – kazuistika
- Masturbační chování žen v ČR − dotazníková studie
- Úspěšná resuscitativní thorakotomie v přednemocniční neodkladné péči
- Dlouhodobá recidiva a komplikace spojené s elektivní operací břišní kýly
Najčítanejšie v tomto čísle
- A daily diary study on maladaptive daydreaming, mind wandering, and sleep disturbances: Examining within-person and between-persons relations
- A 3’ UTR SNP rs885863, a cis-eQTL for the circadian gene VIPR2 and lincRNA 689, is associated with opioid addiction
- A substitution mutation in a conserved domain of mammalian acetate-dependent acetyl CoA synthetase 2 results in destabilized protein and impaired HIF-2 signaling
- Molecular validation of clinical Pantoea isolates identified by MALDI-TOF