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Blood gene expression profiling of an early acetaminophen response

The Pharmacogenomics Journal volume 17, pages 230–236 (2017)Cite this article

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Abstract

Acetaminophen can adversely affect the liver especially when overdosed. We used whole blood as a surrogate to identify genes as potential early indicators of an acetaminophen-induced response. In a clinical study, healthy human subjects were dosed daily with 4 g of either acetaminophen or placebo pills for 7 days and evaluated over the course of 14 days. Alanine aminotransferase (ALT) levels for responders to acetaminophen increased between days 4 and 9 after dosing, and 12 genes were detected with expression profiles significantly altered within 24 h. The early responsive genes separated the subjects by class and dose period. In addition, the genes clustered patients who overdosed on acetaminophen apart from controls and also predicted the exposure classifications with 100% accuracy. The responsive genes serve as early indicators of an acetaminophen exposure, and their gene expression profiles can potentially be evaluated as molecular indicators for further consideration.

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Gene Expression Omnibus

References

  1. Ferner RE, Dear JW, Bateman DN . Management of paracetamol poisoning. BMJ 2011; 342: d2218.

    Article  PubMed  Google Scholar 

  2. Manthripragada AD, Zhou EH, Budnitz DS, Lovegrove MC, Willy ME . Characterization of acetaminophen overdose-related emergency department visits and hospitalizations in the United States. Pharmacoepidemiol Drug Saf 2011; 20: 819–826.

    Article  PubMed  Google Scholar 

  3. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42: 1364–1372.

    Article  CAS  PubMed  Google Scholar 

  4. Nourjah P, Ahmad SR, Karwoski C, Willy M . Estimates of acetaminophen (paracetomal)-associated overdoses in the United States. Pharmacoepidemiol Drug Saf 2006; 15: 398–405.

    Article  PubMed  Google Scholar 

  5. Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137: 947–954.

    Article  PubMed  Google Scholar 

  6. Bronstein AC, Spyker DA, Cantilena LR Jr., Green JL, Rumack BH, Giffin SL 2008 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 26th Annual Report. Clin Toxicol (Phila) 2009 47: 911–1084.

    Article  Google Scholar 

  7. Mitka M . FDA asks physicians to stop prescribing high-dose acetaminophen products. JAMA 2014; 311: 563.

    Article  CAS  PubMed  Google Scholar 

  8. Kuehn BM . FDA focuses on drugs and liver damage: labeling and other changes for acetaminophen. JAMA 2009; 302: 369–371.

    Article  CAS  PubMed  Google Scholar 

  9. Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA 2006; 296: 87–93.

    Article  CAS  PubMed  Google Scholar 

  10. Heard KJ . Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008; 359: 285–292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chou JW, Paules RS, Bushel PR . Systematic variation normalization in microarray data to get gene expression comparison unbiased. J Bioinform Comput Biol 2005; 3: 225–241.

    Article  CAS  PubMed  Google Scholar 

  12. Johnson WE, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 2007; 8: 118–127.

    Article  PubMed  Google Scholar 

  13. Neter J, Kutner MH, Nachtsheim CJ, Wasserman W . Applied Linear Statistical Models. 4th edn. Irwin: Chicago, IL, USA, 1996 xv, 720 p.p.

    Google Scholar 

  14. Storey JD . A direct approach to false discovery rates. J R Stat Soc Series B Stat Methodol 2002; 64: 479–498.

    Article  Google Scholar 

  15. Storey JD . The positive false discovery rate: a Bayesian interpretation and the q-value. Ann Stat 2003; 31: 2013–2035.

    Article  Google Scholar 

  16. Hughes TR, Marton MJ, Jones AR, Roberts CJ, Stoughton R, Armour CD et al. Functional discovery via a compendium of expression profiles. Cell 2000; 102: 109–126.

    Article  CAS  PubMed  Google Scholar 

  17. Hastie T, Hastie T, Tibshirani R, Friedman JH . The Elements of Statistical Learning: Data Mining, Inference, and Prediction. Springer: New York, USA, 2001 xvi, 533 p.pp.

    Book  Google Scholar 

  18. Omer A, Singh P, Yadav NK, Singh RK . An overview of data mining algorithms in drug induced toxicity prediction. Mini Rev Med Chem 2014; 14: 345–354.

    Article  CAS  PubMed  Google Scholar 

  19. Beyer RP, Fry RC, Lasarev MR, McConnachie LA, Meira LB, Palmer VS et al. Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses. Toxicol Sci 2007; 99: 326–337.

    Article  CAS  PubMed  Google Scholar 

  20. Heinloth AN, Boorman GA, Foley JF, Flagler ND, Paules RS . Gene expression analysis offers unique advantages to histopathology in liver biopsy evaluations. Toxicol Pathol 2007; 35: 276–283.

    Article  CAS  PubMed  Google Scholar 

  21. Baken KA, Pennings JL, Jonker MJ, Schaap MM, de Vries A, van Steeg H et al. Overlapping gene expression profiles of model compounds provide opportunities for immunotoxicity screening. Toxicol Appl Pharmacol 2008; 226: 46–59.

    Article  CAS  PubMed  Google Scholar 

  22. Bushel PR . Clustering of mixed data types with application to toxicogenomics. PhD dissertation 2005.

  23. Poulsen HE, Petersen P, Vilstrup H . Quantitative liver function and morphology after paracetamol administration to rats. Eur J Clin Invest 1981; 11: 161–164.

    Article  CAS  PubMed  Google Scholar 

  24. Lewis MJ, Pelham HR . Ligand-induced redistribution of a human KDEL receptor from the Golgi complex to the endoplasmic reticulum. Cell 1992; 68: 353–364.

    Article  CAS  PubMed  Google Scholar 

  25. Handford M, Rodriguez-Furlan C, Orellana A . Nucleotide-sugar transporters: structure, function and roles in vivo. Braz J Med Biol Res 2006; 39: 1149–1158.

    Article  CAS  PubMed  Google Scholar 

  26. Parrado A, Robledo M, Moya-Quiles MR, Marin LA, Chomienne C, Padua RA et al. The promyelocytic leukemia zinc finger protein down-regulates apoptosis and expression of the proapoptotic BID protein in lymphocytes. Proc Natl Acad Sci USA 2004; 101: 1898–1903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Toyonaga T, Hino O, Sugai S, Wakasugi S, Abe K, Shichiri M et al. Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver. Proc Natl Acad Sci USA 1994; 91: 614–618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Krenkel O, Mossanen JC, Tacke F . Immune mechanisms in acetaminophen-induced acute liver failure. Hepatobiliary Surg Nutr 2014; 3: 331–343.

    PubMed  PubMed Central  Google Scholar 

  29. Liu ZX, Kaplowitz N . Role of innate immunity in acetaminophen-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 2006; 2: 493–503.

    Article  CAS  PubMed  Google Scholar 

  30. Masson MJ, Peterson RA, Chung CJ, Graf ML, Carpenter LD, Ambroso JL et al. Lymphocyte loss and immunosuppression following acetaminophen-induced hepatotoxicity in mice as a potential mechanism of tolerance. Chem Res Toxicol 2007; 20: 20–26.

    Article  CAS  PubMed  Google Scholar 

  31. Jaeschke H, Williams CD, Ramachandran A, Bajt ML . Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int 2012; 32: 8–20.

    Article  CAS  PubMed  Google Scholar 

  32. Radici L, Bianchi M, Crinelli R, Magnani M . Ubiquitin C gene: structure, function, and transcriptional regulation. Adv Biosci Biotechnol 2013; 4: 1057–1062.

    Article  Google Scholar 

  33. Nagy G, Kardon T, Wunderlich L, Szarka A, Kiss A, Schaff Z et al. Acetaminophen induces ER dependent signaling in mouse liver. Arch Biochem Biophys 2007; 459: 273–279.

    Article  CAS  PubMed  Google Scholar 

  34. McQueen CA . Comprehensive Toxicology Elsevier Science & Technology Books: San Diego, Saint Louis, USA, 2010.

  35. Yoshida H . ER stress and diseases. FEBS J 2007; 274: 630–658.

    Article  CAS  PubMed  Google Scholar 

  36. Wang K, Zhang S, Marzolf B, Troisch P, Brightman A, Hu Z et al. Circulating microRNAs, potential biomarkers for drug-induced liver injury. Proc Natl Acad Sci USA 2009; 106: 4402–4407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ward J, Kanchagar C, Veksler-Lublinsky I, Lee RC, McGill MR, Jaeschke H et al. Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis. Proc Natl Acad Sci USA 2014; 111: 12169–12174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kumar BS, Chung BC, Kwon OS, Jung BH . Discovery of common urinary biomarkers for hepatotoxicity induced by carbon tetrachloride, acetaminophen and methotrexate by mass spectrometry-based metabolomics. J Appl Toxicol 2012; 32: 505–520.

    Article  CAS  PubMed  Google Scholar 

  39. van Swelm RP, Laarakkers CM, van der Kuur EC, Morava-Kozicz E, Wevers RA, Augustijn KD et al. Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice. PLoS One 2012; 7: e49524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Prot JM, Briffaut AS, Letourneur F, Chafey P, Merlier F, Grandvalet Y et al. Integrated proteomic and transcriptomic investigation of the acetaminophen toxicity in liver microfluidic biochip. PLoS One 2011; 6: e21268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Merrick BA, Bruno ME, Madenspacher JH, Wetmore BA, Foley J, Pieper R et al. Alterations in the rat serum proteome during liver injury from acetaminophen exposure. J Pharmacol Exp Ther 2006; 318: 792–802.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported [in part] by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH, and National Institute of Environmental Health Sciences grant P30ES10126, NIH grants R37 GM38149 and K23 RR21857-01, and The University of North Carolina General Clinical Research Center grant M000046. The raw and preprocessed data for the clinical study are publicly available in the Gene Expression Omnibus (GEO) database under accession number: GSE70784. The raw and preprocessed data for the overdose patient data are publicly available in the GEO database under accession number: GSE70786.

Author information

Author notes

  1. P R Bushel

    Present address: 7Current address: Biostatistics and Computational Biology Branch, NIEHS, Research Triangle Park, NC, USA.,

  2. R D Fannin & K Gerrish

    Present address: 8Current address: Epigenetics and Stem Cell Biology Laboratory, NIEHS, Research Triangle Park, NC, USA.,

  3. R S Paules

    Present address: 9Current address: Bio-Molecular Screening Branch, NIEHS, Research Triangle Park, NC, USA.,

Authors and Affiliations

  1. Microarray and Genome Informatics Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    P R Bushel

  2. Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    P R Bushel

  3. Molecular Genomics Core, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    R D Fannin, K Gerrish & R S Paules

  4. Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA

    R D Fannin, K Gerrish & R S Paules

  5. The Hamner Institute for Health Sciences, Research Triangle Park, NC, USA

    P B Watkins

  6. Department of Medicine, University of North Carolina, Chapel Hill, NC, USA

    P B Watkins

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Correspondence to P R Bushel or R S Paules.

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Competing interests

PBW has served as a consultant for McNeil Corporation, a major manufacturer of acetaminophen-containing products.

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Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

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Bushel, P., Fannin, R., Gerrish, K. et al. Blood gene expression profiling of an early acetaminophen response. Pharmacogenomics J 17, 230–236 (2017). https://doi.org/10.1038/tpj.2016.8

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