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Expression Levels of GABA-A Receptor Subunit Alpha 3, Gabra3 and Lipoprotein Lipase, Lpl Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity

  • Kim, Minjeong (College of Pharmacy, Ewha Womans University) ;
  • Yun, Jun-Won (Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital) ;
  • Shin, Kyeho (Department of Beauty Coordination, Suwon Science College) ;
  • Cho, Yejin (Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine) ;
  • Yang, Mijeong (Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine) ;
  • Nam, Ki Taek (Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine) ;
  • Lim, Kyung-Min (College of Pharmacy, Ewha Womans University)
  • Received : 2016.04.05
  • Accepted : 2016.05.11
  • Published : 2017.03.01

Abstract

Drug-induced liver injury (DILI) is the serious and fatal drug-associated adverse effect, but its incidence is very low and individual variation in severity is substantial. Acetaminophen (APAP)-induced liver injury accounts for >50% of reported DILI cases but little is known for the cause of individual variations in the severity. Intrinsic genetic variation is considered a key element but the identity of the genes was not well-established. Here, pre-biopsy method and microarray technique was applied to uncover the key genes for APAP-induced liver injury in mice, and a cause and effect experiment employing quantitative real-time PCR was conducted to confirm the correlation between the uncovered genes and APAP-induced hepatotoxicity. We identified the innately and differentially expressed genes of mice susceptible to APAP-induced hepatotoxicity in the pre-biopsied liver tissue before APAP treatment through microarray analysis of the global gene expression profiles (Affymetrix $GeneChip^{(R)}$ Mouse Gene 1.0 ST for 28,853 genes). Expression of 16 genes including Gdap10, Lpl, Gabra3 and Ccrn4l were significantly different (t-test: FDR <10%) more than 1.5 fold in the susceptible animals than resistant. To confirm the association with the susceptibility to APAP-induced hepatotoxicity, another set of animals were measured for the expression level of selected 4 genes (higher two and lower two genes) in the liver pre-biopsy and their sensitivity to APAP-induced hepatotoxicity was evaluated by post hoc. Notably, the expressions of Gabra3 and Lpl were significantly correlated with the severity of liver injury (p<0.05) demonstrating that these genes may be linked to the susceptibility to APAP-induced hepatotoxicity.

Keywords

References

  1. Baron, A. D., Brechtel, G., Wallace, P. and Edelman, S. V. (1988) Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am. J. Physiol. 255, E769-E774.
  2. Bessems, J. G. and Vermeulen, N. P. (2001) Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit. Rev. Toxicol. 31, 55-138. https://doi.org/10.1080/20014091111677
  3. Biju, M. P., Pyroja, S., Rajeshkumar, N. V. and Paulose, C. S. (2001) Hepatic GABA(A) receptor functional regulation during rat liver cell proliferation. Hepatol. Res. 21, 136-146. https://doi.org/10.1016/S1386-6346(01)00092-4
  4. Bozogluer, E., Madenoglu, H., Aksu, R., Bicer, C., Yazici, C. and Boyaci, A. (2012) The effect of different doses of flumazenil on acetaminophen toxicity in rats. Bratisl. Lek. Listy 113, 525-528.
  5. Chang, C. Y. and Schiano, T. D. (2007) Review article: drug hepatotoxicity. Aliment. Pharmacol. Ther. 25, 1135-1151. https://doi.org/10.1111/j.1365-2036.2007.03307.x
  6. Clark, S. J., Shojaee-Moradie, F., Croos, P., Seed, P. T., Umpleby, A. M., Wendon, J. A. and Miell, J. (2001) Temporal changes in insulin sensitivity following the development of acute liver failure secondary to acetaminophen. Hepatology 34, 109-115. https://doi.org/10.1016/S0168-8278(01)81268-X
  7. Draghici, S., Khatri, P., Eklund, A. C. and Szallasi, Z. (2006) Reliability and reproducibility issues in DNA microarray measurements. Trends Genet. 22, 101-109. https://doi.org/10.1016/j.tig.2005.12.005
  8. Fausto, N., Campbell, J. S. and Riehle, K. J. (2006) Liver regeneration. Hepatology 43, S45-S53. https://doi.org/10.1002/hep.20969
  9. Goldberg, I. J. (1996) Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J. Lipid Res. 37, 693-707.
  10. Green, C. B., Douris, N., Kojima, S., Strayer, C. A., Fogerty, J., Lourim, D., Keller, S. R. and Besharse, J. C. (2007) Loss of Nocturnin, a circadian deadenylase, confers resistance to hepatic steatosis and diet-induced obesity. Proc. Natl. Acad. Sci. U.S.A. 104, 9888-9893. https://doi.org/10.1073/pnas.0702448104
  11. Gutschner, T., Hammerle, M., Eissmann, M., Hsu, J., Kim, Y., Hung, G., Revenko, A., Arun, G., Stentrup, M., Gross, M., Zornig, M., MacLeod, A. R., Spector, D. L. and Diederichs, S. (2013) The Noncoding RNA MALAT1 Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells. Cancer Res. 73, 1180-1189. https://doi.org/10.1158/0008-5472.CAN-12-2850
  12. Hinson, J. A., Roberts, D. W. and James, L. P. (2010) Mechanisms of acetaminophen-induced liver necrosis. Handb. Exp. Pharmacol. 196, 369-405.
  13. Ji, P., Diederichs, S., Wang, W. B., Boing, S., Metzger, R., Schneider, P. M., Tidow, N., Brandt, B., Buerger, H., Bulk, E., Thomas, M., Berdel, W. E., Serve, H. and Muller-Tidow, C. (2003) MALAT-1, a novel noncoding RNA, and thymosin beta 4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22, 8031-8041. https://doi.org/10.1038/sj.onc.1206928
  14. Johnsen, S. A., Subramaniam, M., Janknecht, R. and Spelsberg, T. C. (2002) TGF beta inducible early gene enhances TGF beta/Smaddependent transcriptional responses. Oncogene 21, 5783-5790. https://doi.org/10.1038/sj.onc.1205681
  15. Kim, J. K., Fillmore, J. J., Chen, Y., Yu, C., Moore, I. K., Pypaert, M., Lutz, E. P., Kako, Y., Velez-Carrasco, W., Goldberg, I. J., Breslow, J. L. and Shulman, G. I. (2001) Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc. Natl. Acad. Sci. U.S.A. 98, 7522-7527. https://doi.org/10.1073/pnas.121164498
  16. Krenzelok, E. P. (2009) The FDA Acetaminophen Advisory Committee Meeting - what is the future of acetaminophen in the United States? The perspective of a committee member. Clin. Toxicol. (Phila.) 47, 784-789. https://doi.org/10.1080/15563650903232345
  17. Larson, A. M., Polson, J., Fontana, R. J., Davern, T. J., Lalani, E., Hynan, L. S., Reisch, J. S., Schiodt, F. V., Ostapowicz, G., Shakil, A. O. and Lee, W. M. (2005) Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 42, 1364-1372. https://doi.org/10.1002/hep.20948
  18. Lazarou, J., Pomeranz, B. H. and Corey, P. N. (1998) Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279, 1200-1205. https://doi.org/10.1001/jama.279.15.1200
  19. Lee, S. S., Buters, J. T., Pineau, T., Fernandez-Salguero, P. and Gonzalez, F. J. (1996) Role of CYP2E1 in the hepatotoxicity of acetaminophen. J. Biol. Chem. 271, 12063-12067. https://doi.org/10.1074/jbc.271.20.12063
  20. Lewis, J. H. (2000) Drug-induced liver disease. Med. Clin. North Am. 84, 1275-1311. https://doi.org/10.1016/S0025-7125(05)70287-X
  21. Liu, H., Nakagawa, T., Kanematsu, T., Uchida, T. and Tsuji, S. (1999) Isolation of 10 differentially expressed cDNAs in differentiated Neuro2a cells induced through controlled expression of the GD3 synthase gene. J. Neurochem. 72, 1781-1790.
  22. Liu, H. H., Lu, P., Guo, Y. Y., Farrell, E., Zhang, X., Zheng, M., Bosano, B., Zhang, Z., Allard, J., Liao, G., Fu, S., Chen, J., Dolim, K., Kuroda, A., Usuka, J., Cheng, J., Tao, W., Welch, K., Liu, Y., Pease, J., de Keczer, S. A., Masjedizadeh, M., Hu, J. S., Weller, P., Garrow, T. and Peltz, G. (2010) An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity. Genome Res. 20, 28-35. https://doi.org/10.1101/gr.097212.109
  23. Lu, X. Y., Hu, B., Zheng, J., Ji, C., Fan, X. H. and Gao, Y. (2015) Predose and postdose blood gene expression profiles identify the individuals susceptible to acetaminophen-induced liver injury in rats. PLoS ONE 10, e0141750. https://doi.org/10.1371/journal.pone.0141750
  24. Michalopoulos, G. K. (2007) Liver regeneration. J. Cell. Physiol. 213, 286-300. https://doi.org/10.1002/jcp.21172
  25. Moe, M., Lien, S., Bendixen, C., Hedegaard, J., Hornshoj, H., Berget, I., Meuwissen, T. H. and Grindflek, E. (2008) Gene expression profiles in liver of pigs with extreme high and low levels of androstenone. BMC Vet. Res. 4, 29. https://doi.org/10.1186/1746-6148-4-29
  26. Oh, J.-H., Yoon, H.-J., Lim, J.-S., Park, H.-J., Cho, J.-W., Kwon, M.-S. and Yoon, S.-J. (2009) Analysis of Gene Expression in 4, 4'-Methylenedianiline-induced Acute Hepatotoxicity. Toxicol. Res. 25, 85-92. https://doi.org/10.5487/TR.2009.25.2.085
  27. Ostapowicz, G., Fontana, R. J., Schiodt, F. V., Larson, A., Davern, T. J., Han, S. H., McCashland, T. M., Shakil, A. O., Hay, J. E., Hynan, L., Crippin, J. S., Blei, A. T., Samuel, G., Reisch, J. and Lee, W. M. (2002) Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann. Intern. Med. 137, 947-954. https://doi.org/10.7326/0003-4819-137-12-200212170-00007
  28. Park, A. The FDA's painkiller warning: how to avoid taking too much [Internet]. TIME; 2006 Dec 20. Available from: http://content.time.com/time/health/article/0,8599,1572012,00.html.
  29. Prescott, L. F., Park, J., Ballantyne, A., Adriaenssens, P. and Proudfoot, A. T. (1977) Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet 2, 432-434.
  30. Reuben, A., Koch, D. G. and Lee, W. M. (2010) Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 52, 2065-2076. https://doi.org/10.1002/hep.23937
  31. Saha, B. and Nandi, D. (2009) Farnesyltransferase inhibitors reduce ras activation and ameliorate acetaminophen-induced liver injury in mice. Hepatology 50, 1547-1557. https://doi.org/10.1002/hep.23180
  32. Sanaka, M., Kuyama, Y. and Yamanaka, M. (1998) Guide for judicious use of the paracetamol absorption technique in a study of gastric emptying rate of liquids. J. Gastroenterol. 33, 785-791. https://doi.org/10.1007/s005350050177
  33. Shin, J. H., Lee, C. W., Oh, S. J., Yun, J., Kang, M. R., Han, S. B., Park, H., Jung, J. C., Chung, Y. H. and Kang, J. S. (2014) Hepatoprotective Effect of Aged Black Garlic Extract in Rodents. Toxicol. Res. 30, 49-54. https://doi.org/10.5487/TR.2014.30.1.049
  34. Stamper, B. D., Bammler, T. K., Beyer, R. P., Farin, F. M. and Nelson, S. D. (2010) Differential regulation of mitogen-activated protein kinase pathways by acetaminophen and its nonhepatotoxic regioisomer 3'-hydroxyacetanilide in TAMH cells. Toxicol. Sci. 116, 164-173. https://doi.org/10.1093/toxsci/kfq100
  35. Stephens, C., Lucena, M. I. and Andrade, R. J. (2012) Genetic variations in drug-induced liver injury (DILI): resolving the puzzle. Front. Genet. 3, 253.
  36. Umbright, C., Sellamuthu, R., Li, S. Q., Kashon, M., Luster, M. and Joseph, P. (2010) Blood gene expression markers to detect and distinguish target organ toxicity. Mol. Cell. Biochem. 335, 223-234. https://doi.org/10.1007/s11010-009-0272-5
  37. Wang, H. and Eckel, R. H. (2009) Lipoprotein lipase: from gene to obesity. Am. J. Physiol. Endocrinol. Metab. 297, E271-E288. https://doi.org/10.1152/ajpendo.90920.2008
  38. Watkins, P. B., Kaplowitz, N., Slattery, J. T., Colonese, C. R., Colucci, S. V., Stewart, P. W. and Harris, S. C. (2006) Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 296, 87-93. https://doi.org/10.1001/jama.296.1.87
  39. Watson, W. A., Litovitz, T. L., Klein-Schwartz, W., Rodgers, G. C., Youniss, J., Reid, N., Rouse, W. G., Rembert, R. S. and Borys, D. (2004) 2003 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am. J. Emerg. Med. 22, 335-404. https://doi.org/10.1016/j.ajem.2004.06.001
  40. Yun, J. W., Kim, C. W., Bae, I. H., Park, Y. H., Chung, J. H., Lim, K. M. and Kang, K. S. (2009) Determination of the key innate genes related to individual variation in carbon tetrachloride-induced hepatotoxicity using a pre-biopsy procedure. Toxicol. Appl. Pharmacol. 239, 55-63. https://doi.org/10.1016/j.taap.2009.05.018
  41. Yun, J. W., Kim, C. W., Bae, I. H., Park, Y. H., Chung, J. H., Lim, K. M. and Kang, K. S. (2010) Expression levels of pituitary tumor transforming 1 and glutathione-S-transferase theta 3 are associated with the individual susceptibility to D-galactosamine-induced hepatotoxicity. Toxicol. Appl. Pharmacol. 242, 91-99. https://doi.org/10.1016/j.taap.2009.09.017
  42. Yun, J. W., Kim, M., Cho, S. D., Lee, J. Y., Bae, O. N. and Lim, K. M. (2014) Highly expressed protein kinase A inhibitor alpha and suppression of protein kinase A may potentiate acetaminophen-induced hepatotoxicity. Toxicol. Lett. 229, 59-65. https://doi.org/10.1016/j.toxlet.2014.06.010

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