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. 1998 Feb 15;330(Pt 1):73–79. doi: 10.1042/bj3300073

Ischaemia and reperfusion injury of rat liver increases expression of glutathione S-transferase A1/A2 in zone 3 of the hepatic lobule.

G D Branum 1, N Selim 1, X Liu 1, R Whalen 1, T D Boyer 1
PMCID: PMC1219110  PMID: 9461493

Abstract

Effects of ischaemia-reperfusion injury (I/R) of liver on expression of rat glutathione S-transferase (rGST) isoenzymes that metabolize products of oxidative stress were examined. Rats underwent lobar liver ischaemia for 30 min followed by reperfusion. In ischaemic lobes, rGSTA1/A2 transcript levels increased significantly 12 h after I/R (2.94-fold) and protein levels increased significantly at 24 h (1.45-fold); increased transcript levels were also observed in nonischaemic lobes (1.78-fold). Superoxide dismutase prevented I/R and the increases in transcript and protein levels in ischaemic and non-ischaemic lobes. By in-situ hybridization, increases in transcript levels at 6 h were present in zones 2 and 3 of the ischaemic lobes and peaked at 12 h (2.5-fold zone 2, 4.5-fold zone 3). Significant increases in transcript levels also were observed at 24 h in zones 2 (2.0-fold) and 3 (2.9-fold) of non-ischaemic lobes. Nuclear run-off assays showed a 1.8-fold increase in rGSTA1/A2 transcription rates in ischaemic lobes at 3 h. We conclude that I/R causes increased rGSTA1/A2 expression in the zone of the hepatic lobule most susceptible to oxidative injury and that this expression may be an important defence against injury.

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Selected References

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  1. Arthur J. R., Morrice P. C., Nicol F., Beddows S. E., Boyd R., Hayes J. D., Beckett G. J. The effects of selenium and copper deficiencies on glutathione S-transferase and glutathione peroxidase in rat liver. Biochem J. 1987 Dec 1;248(2):539–544. doi: 10.1042/bj2480539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bergelson S., Pinkus R., Daniel V. Intracellular glutathione levels regulate Fos/Jun induction and activation of glutathione S-transferase gene expression. Cancer Res. 1994 Jan 1;54(1):36–40. [PubMed] [Google Scholar]
  3. Boyer T. D., Kenney W. C., Zakim D. Structural, functional and hybridization studies of the glutathione S-transferases of rat liver. Biochem Pharmacol. 1983 Jun 15;32(12):1843–1850. doi: 10.1016/0006-2952(83)90048-5. [DOI] [PubMed] [Google Scholar]
  4. Boyer T. D. The glutathione S-transferases: an update. Hepatology. 1989 Mar;9(3):486–496. doi: 10.1002/hep.1840090324. [DOI] [PubMed] [Google Scholar]
  5. Chang M., Burgess J. R., Scholz R. W., Reddy C. C. The induction of specific rat liver glutathione S-transferase subunits under inadequate selenium nutrition causes an increase in prostaglandin F2 alpha formation. J Biol Chem. 1990 Apr 5;265(10):5418–5423. [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Coles B., Ketterer B. The role of glutathione and glutathione transferases in chemical carcinogenesis. Crit Rev Biochem Mol Biol. 1990;25(1):47–70. doi: 10.3109/10409239009090605. [DOI] [PubMed] [Google Scholar]
  8. Colletti L. M., Kunkel S. L., Walz A., Burdick M. D., Kunkel R. G., Wilke C. A., Strieter R. M. The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat. Hepatology. 1996 Mar;23(3):506–514. doi: 10.1002/hep.510230315. [DOI] [PubMed] [Google Scholar]
  9. Ding G. J., Ding V. D., Rodkey J. A., Bennett C. D., Lu A. Y., Pickett C. B. Rat liver glutathione S-transferases. DNA sequence analysis of a Yb2 cDNA clone and regulation of the Yb1 and Yb2 mRNAs by phenobarbital. J Biol Chem. 1986 Jun 15;261(17):7952–7957. [PubMed] [Google Scholar]
  10. Ding V. D., Pickett C. B. Transcriptional regulation of rat liver glutathione S-transferase genes by phenobarbital and 3-methylcholanthrene. Arch Biochem Biophys. 1985 Aug 1;240(2):553–559. doi: 10.1016/0003-9861(85)90062-1. [DOI] [PubMed] [Google Scholar]
  11. Halliwell B. Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med. 1991 Sep 30;91(3C):14S–22S. doi: 10.1016/0002-9343(91)90279-7. [DOI] [PubMed] [Google Scholar]
  12. Hayashi H., Chaudry I. H., Clemens M. G., Baue A. E. Hepatic ischemia models for determining the effects of ATP-MgCl2 treatment. J Surg Res. 1986 Feb;40(2):167–175. doi: 10.1016/0022-4804(86)90119-8. [DOI] [PubMed] [Google Scholar]
  13. Hayes J. D., Pulford D. J. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol. 1995;30(6):445–600. doi: 10.3109/10409239509083491. [DOI] [PubMed] [Google Scholar]
  14. Jaeschke H., Smith C. V., Mitchell J. R. Reactive oxygen species during ischemia-reflow injury in isolated perfused rat liver. J Clin Invest. 1988 Apr;81(4):1240–1246. doi: 10.1172/JCI113441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jaeschke H. The therapeutic potential of glutathione in hepatic ischemia-reperfusion injury. Transplantation. 1993 Jul;56(1):256–257. doi: 10.1097/00007890-199307000-00057. [DOI] [PubMed] [Google Scholar]
  16. Kawamoto S., Inoue M., Tashiro S., Morino Y., Miyauchi Y. Inhibition of ischemia and reflow-induced liver injury by an SOD derivative that circulates bound to albumin. Arch Biochem Biophys. 1990 Feb 15;277(1):160–165. doi: 10.1016/0003-9861(90)90565-g. [DOI] [PubMed] [Google Scholar]
  17. Kobayashi H., Nonami T., Kurokawa T., Sugiyama S., Ozawa T., Takagi H. Mechanism and prevention of ischemia-reperfusion-induced liver injury in rats. J Surg Res. 1991 Sep;51(3):240–244. doi: 10.1016/0022-4804(91)90101-q. [DOI] [PubMed] [Google Scholar]
  18. Kren B. T., Trembley J. H., Steer C. J. Alterations in mRNA stability during rat liver regeneration. Am J Physiol. 1996 May;270(5 Pt 1):G763–G777. doi: 10.1152/ajpgi.1996.270.5.G763. [DOI] [PubMed] [Google Scholar]
  19. Lee S. J., Boyer T. D. The effect of hepatic regeneration on the expression of the glutathione S-transferases. Biochem J. 1993 Jul 1;293(Pt 1):137–142. doi: 10.1042/bj2930137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lee S. J., Friedman S. L., Whalen R., Boyer T. D. Cellular sources of glutathione S-transferase P in primary cultured rat hepatocytes: localization by in situ hybridization. Biochem J. 1994 Apr 1;299(Pt 1):79–83. doi: 10.1042/bj2990079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mannervik B., Alin P., Guthenberg C., Jensson H., Tahir M. K., Warholm M., Jörnvall H. Identification of three classes of cytosolic glutathione transferase common to several mammalian species: correlation between structural data and enzymatic properties. Proc Natl Acad Sci U S A. 1985 Nov;82(21):7202–7206. doi: 10.1073/pnas.82.21.7202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mannervik B., Danielson U. H. Glutathione transferases--structure and catalytic activity. CRC Crit Rev Biochem. 1988;23(3):283–337. doi: 10.3109/10409238809088226. [DOI] [PubMed] [Google Scholar]
  23. Meyer D. J., Coles B., Pemble S. E., Gilmore K. S., Fraser G. M., Ketterer B. Theta, a new class of glutathione transferases purified from rat and man. Biochem J. 1991 Mar 1;274(Pt 2):409–414. doi: 10.1042/bj2740409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Neuhold L. A., Shirayoshi Y., Ozato K., Jones J. E., Nebert D. W. Regulation of mouse CYP1A1 gene expression by dioxin: requirement of two cis-acting elements during induction. Mol Cell Biol. 1989 Jun;9(6):2378–2386. doi: 10.1128/mcb.9.6.2378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Okuda M., Lee H. C., Chance B., Kumar C. Glutathione and ischemia-reperfusion injury in the perfused rat liver. Free Radic Biol Med. 1992;12(4):271–279. doi: 10.1016/0891-5849(92)90114-v. [DOI] [PubMed] [Google Scholar]
  26. Paulson K. E., Darnell J. E., Jr, Rushmore T., Pickett C. B. Analysis of the upstream elements of the xenobiotic compound-inducible and positionally regulated glutathione S-transferase Ya gene. Mol Cell Biol. 1990 May;10(5):1841–1852. doi: 10.1128/mcb.10.5.1841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pickett C. B., Lu A. Y. Glutathione S-transferases: gene structure, regulation, and biological function. Annu Rev Biochem. 1989;58:743–764. doi: 10.1146/annurev.bi.58.070189.003523. [DOI] [PubMed] [Google Scholar]
  28. Pickett C. B., Telakowski-Hopkins C. A., Ding G. J., Argenbright L., Lu A. Y. Rat liver glutathione S-transferases. Complete nucleotide sequence of a glutathione S-transferase mRNA and the regulation of the Ya, Yb, and Yc mRNAs by 3-methylcholanthrene and phenobarbital. J Biol Chem. 1984 Apr 25;259(8):5182–5188. [PubMed] [Google Scholar]
  29. Pinkus R., Weiner L. M., Daniel V. Role of oxidants and antioxidants in the induction of AP-1, NF-kappaB, and glutathione S-transferase gene expression. J Biol Chem. 1996 Jun 7;271(23):13422–13429. doi: 10.1074/jbc.271.23.13422. [DOI] [PubMed] [Google Scholar]
  30. Reddy K. V., Anuradha D., Kumar T. C., Reddanna P. Induction of Ya1 subunit of rat hepatic glutathione S-transferases by exercise-induced oxidative stress. Arch Biochem Biophys. 1995 Oct 20;323(1):6–10. doi: 10.1006/abbi.1995.0002. [DOI] [PubMed] [Google Scholar]
  31. Rushmore T. H., Morton M. R., Pickett C. B. The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity. J Biol Chem. 1991 Jun 25;266(18):11632–11639. [PubMed] [Google Scholar]
  32. Rushmore T. H., Pickett C. B. Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. J Biol Chem. 1990 Aug 25;265(24):14648–14653. [PubMed] [Google Scholar]
  33. Schmidt K. N., Traenckner E. B., Meier B., Baeuerle P. A. Induction of oxidative stress by okadaic acid is required for activation of transcription factor NF-kappa B. J Biol Chem. 1995 Nov 10;270(45):27136–27142. doi: 10.1074/jbc.270.45.27136. [DOI] [PubMed] [Google Scholar]
  34. Sen C. K., Packer L. Antioxidant and redox regulation of gene transcription. FASEB J. 1996 May;10(7):709–720. doi: 10.1096/fasebj.10.7.8635688. [DOI] [PubMed] [Google Scholar]
  35. Sies H. Oxidative stress: from basic research to clinical application. Am J Med. 1991 Sep 30;91(3C):31S–38S. doi: 10.1016/0002-9343(91)90281-2. [DOI] [PubMed] [Google Scholar]
  36. Silver G., Krauter K. S. Aryl hydrocarbon induction of rat cytochrome P-450d results from increased precursor RNA processing. Mol Cell Biol. 1990 Dec;10(12):6765–6768. doi: 10.1128/mcb.10.12.6765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Singhal S. S., Saxena M., Ahmad H., Awasthi S., Haque A. K., Awasthi Y. C. Glutathione S-transferases of human lung: characterization and evaluation of the protective role of the alpha-class isozymes against lipid peroxidation. Arch Biochem Biophys. 1992 Dec;299(2):232–241. doi: 10.1016/0003-9861(92)90269-3. [DOI] [PubMed] [Google Scholar]
  38. Suguoka Y., Kano T., Okuda A., Sakai M., Kitagawa T., Muramatsu M. Cloning and the nucleotide sequence of rat glutathione S-transferase P cDNA. Nucleic Acids Res. 1985 Sep 11;13(17):6049–6057. doi: 10.1093/nar/13.17.6049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tacchini L., Radice L., Pogliaghi G., Bernelli-Zazzera A. Differential activation of heat shock and nuclear factor kappaB transcription factors in postischemic reperfused rat liver. Hepatology. 1997 Jul;26(1):186–191. doi: 10.1053/jhep.1997.v26.pm0009214468. [DOI] [PubMed] [Google Scholar]
  40. Thanos D., Maniatis T. NF-kappa B: a lesson in family values. Cell. 1995 Feb 24;80(4):529–532. doi: 10.1016/0092-8674(95)90506-5. [DOI] [PubMed] [Google Scholar]
  41. Voss S. H., Park Y., Kwon S. O., Whalen R., Boyer T. D. Role of interleukin 6 and corticosteroids in the regulation of expression of glutathione S-transferases in primary cultures of rat hepatocytes. Biochem J. 1996 Jul 15;317(Pt 2):627–632. doi: 10.1042/bj3170627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Waxman D. J., Sundseth S. S., Srivastava P. K., Lapenson D. P. Gene-specific oligonucleotide probes for alpha, mu, pi, and microsomal rat glutathione S-transferases: analysis of liver transferase expression and its modulation by hepatic enzyme inducers and platinum anticancer drugs. Cancer Res. 1992 Oct 15;52(20):5797–5802. [PubMed] [Google Scholar]
  43. Wilcox J. N., Smith K. M., Schwartz S. M., Gordon D. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2839–2843. doi: 10.1073/pnas.86.8.2839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wilcox J. N., Smith K. M., Williams L. T., Schwartz S. M., Gordon D. Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest. 1988 Sep;82(3):1134–1143. doi: 10.1172/JCI113671. [DOI] [PMC free article] [PubMed] [Google Scholar]

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