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Frontiers in physiology
2012;3 462.

Modeling drug- and chemical-induced hepatotoxicity with systems biology approaches.

Sudin Bhattacharya, Lisl K M Shoda, Qiang Zhang, Courtney G Woods, Brett A Howell, Scott Q Siler, Jeffrey L Woodhead, Yuching Yang, Patrick McMullen, Paul B Watkins, Melvin E Andersen
Author Information
  1. Sudin Bhattacharya: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences Research Triangle Park, NC, USA.
PMID: 23248599 DOI: 10.3389/fphys.2012.00462

Abstract

We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of "toxicity pathways" is described in the context of the 2007 US National Academies of Science report, "Toxicity testing in the 21st Century: A Vision and A Strategy." Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity) - a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular "virtual tissue" model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the aryl hydrocarbon receptor toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsym™) to understand drug-induced liver injury (DILI), the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

Keywords

chemical toxicity computational toxicology drug toxicity multi-scale modeling systems toxicology toxicity pathways virtual liver

References

  1. BMC Syst Biol. 2011 Jul 11;5:109 [PMID: 21745399]
  2. Math Comput Model. 2009 Jan 1;49(1-2):307-319 [PMID: 20047002]
  3. Environ Health Perspect. 1993 Dec;101(7):634-42 [PMID: 8143597]
  4. J Chem Phys. 2004 Aug 15;121(7):3347-8 [PMID: 15291645]
  5. Hepatology. 1995 Feb;21(2):477-86 [PMID: 7843722]
  6. PLoS Comput Biol. 2007 Mar 2;3(3):e24 [PMID: 17335342]
  7. Carcinogenesis. 1987 Oct;8(10):1433-7 [PMID: 2443263]
  8. Nature. 2008 May 8;453(7192):150-3 [PMID: 18464714]
  9. Am J Pathol. 1991 Sep;139(3):535-52 [PMID: 1716045]
  10. J Pathol. 1975 Nov;117(3):169-81 [PMID: 1214189]
  11. Toxicol Ind Health. 2010 Mar;26(2):89-104 [PMID: 20103580]
  12. PLoS Comput Biol. 2010 Apr 22;6(4):e1000756 [PMID: 20421935]
  13. Dig Liver Dis. 2009 Jul;41(7):455-62 [PMID: 19403350]
  14. Singapore Med J. 2010 May;51(5):389-98 [PMID: 20593143]
  15. Crit Rev Toxicol. 1997 Mar;27(2):109-34 [PMID: 9099515]
  16. Am J Physiol Gastrointest Liver Physiol. 2001 Jun;280(6):G1274-9 [PMID: 11352821]
  17. Pharmacol Ther. 1996;71(1-2):193-223 [PMID: 8910955]
  18. Cell Mol Life Sci. 2004 Feb;61(4):393-416 [PMID: 14999402]
  19. Annu Rev Pharmacol Toxicol. 1982;22:517-54 [PMID: 6282188]
  20. Science. 2002 Oct 25;298(5594):799-804 [PMID: 12399584]
  21. IEEE Trans Nanobioscience. 2004 Sep;3(3):153-63 [PMID: 15473067]
  22. Hepatology. 1999 Jan;29(1):161-5 [PMID: 9862862]
  23. Science. 2002 Aug 9;297(5583):1018-23 [PMID: 12169734]
  24. J Lab Clin Med. 1985 May;105(5):619-24 [PMID: 3989355]
  25. Nat Rev Drug Discov. 2007 Nov;6(11):871-80 [PMID: 17932492]
  26. J Theor Biol. 2009 Jul 7;259(1):67-83 [PMID: 19285513]
  27. Genome Res. 2006 May;16(5):595-605 [PMID: 16606705]
  28. Mol Pharmacol. 2008 Feb;73(2):387-98 [PMID: 18000031]
  29. J Pharmacol Exp Ther. 1997 Jan;280(1):506-11 [PMID: 8996235]
  30. Bioinformatics. 2012 Apr 15;28(8):1130-5 [PMID: 22355081]
  31. Cancer Res. 2000 Dec 15;60(24):6911-20 [PMID: 11156390]
  32. Mol Endocrinol. 2008 Jan;22(1):10-22 [PMID: 17901129]
  33. Shock. 2001 Oct;16(4):266-73 [PMID: 11580108]
  34. Nat Rev Genet. 2005 Jun;6(6):451-64 [PMID: 15883588]
  35. Prog Cell Cycle Res. 2003;5:261-7 [PMID: 14593720]
  36. J Mol Biol. 2006 Mar 10;356(5):1073-81 [PMID: 16406067]
  37. Ann Emerg Med. 2009 Oct;54(4):606-14 [PMID: 19556028]
  38. Carcinogenesis. 1995 Nov;16(11):2807-11 [PMID: 7586202]
  39. J Math Biol. 2009 Apr;58(4-5):545-59 [PMID: 18787828]
  40. Semin Liver Dis. 2003 Nov;23(4):385-96 [PMID: 14722815]
  41. Natl Toxicol Program Tech Rep Ser. 2006 May;(529):4-168 [PMID: 16835634]
  42. Nat Rev Mol Cell Biol. 2010 Jun;11(6):414-26 [PMID: 20495582]
  43. Oncogene. 2008 Apr 3;27(15):2198-207 [PMID: 17952121]
  44. Cancer Res. 1976 Apr;36(4):1211-7 [PMID: 177202]
  45. Natl Toxicol Program Tech Rep Ser. 2006 Sep;(526):1-180 [PMID: 17342195]
  46. Epigenomics. 2011 Aug;3(4):471-85 [PMID: 22126206]
  47. J Mol Biol. 2003 Nov 21;334(2):197-204 [PMID: 14607112]
  48. Biochem Soc Trans. 2003 Dec;31(Pt 6):1526-9 [PMID: 14641104]
  49. Am J Surg Pathol. 2001 Nov;25(11):1388-96 [PMID: 11684955]
  50. Cell. 2005 Sep 23;122(6):947-56 [PMID: 16153702]
  51. Physiol Rev. 2007 Jul;87(3):905-31 [PMID: 17615392]
  52. J Mol Biol. 2002 Nov 8;323(5):785-93 [PMID: 12417193]
  53. Nat Rev Genet. 2007 Jun;8(6):450-61 [PMID: 17510665]
  54. J Biol Chem. 2004 Jun 4;279(23):23847-50 [PMID: 15028720]
  55. J Toxicol Environ Health B Crit Rev. 2010 Feb;13(2-4):314-28 [PMID: 20574905]
  56. Proc Natl Acad Sci U S A. 2010 May 4;107(18):8248-53 [PMID: 20404163]
  57. Hepatology. 1997 Jun;25(6):1539-42 [PMID: 9185779]
  58. Genes Dev. 2008 Nov 1;22(21):2941-52 [PMID: 18981473]
  59. Toxicol Sci. 2009 Oct;111(2):202-25 [PMID: 19567883]
  60. Pflugers Arch. 2007 Feb;453(5):661-73 [PMID: 16586096]
  61. Chromosoma. 2010 Oct;119(5):479-84 [PMID: 20625907]
  62. Annu Rev Physiol. 2005;67:225-57 [PMID: 15709958]
  63. Ann Emerg Med. 1991 Oct;20(10):1058-63 [PMID: 1928874]
  64. Immunol Cell Biol. 2010 Feb;88(2):172-9 [PMID: 19884904]
  65. Nucleic Acids Res. 2010 May;38(9):2839-50 [PMID: 20110263]
  66. Toxicol Appl Pharmacol. 1990 May;103(3):399-410 [PMID: 2160135]
  67. Toxicol Lett. 1993 May;68(1-2):177-89 [PMID: 8516763]
  68. J Hepatol. 2004 Feb;40(2):298-304 [PMID: 14739102]
  69. Nat Genet. 2002 May;31(1):64-8 [PMID: 11967538]
  70. Science. 1985 Mar 22;227(4693):1499-502 [PMID: 3856321]
  71. Science. 1999 Jan 15;283(5400):381-7 [PMID: 9888852]
  72. BMC Syst Biol. 2008 Dec 23;2:110 [PMID: 19105850]
  73. J Chem Phys. 2005 Feb 1;122(5):54103 [PMID: 15740306]
  74. J Pharmacol Exp Ther. 2012 Aug;342(2):529-40 [PMID: 22593093]
  75. Nat Genet. 2006 Nov;38(11):1289-97 [PMID: 17013392]
  76. Science. 2008 Apr 4;320(5872):65-8 [PMID: 18388284]
  77. PLoS Genet. 2007 Jun;3(6):e94 [PMID: 17559307]
  78. Toxicol Sci. 2010 May;115(1):51-65 [PMID: 20123757]
  79. Arch Toxicol. 1994;68(6):349-57 [PMID: 8092926]
  80. Hepatology. 2006 Feb;43(2 Suppl 1):S45-53 [PMID: 16447274]
  81. J Theor Biol. 2003 Jul 7;223(1):1-18 [PMID: 12782112]
  82. Nature. 1980 Jan 24;283(5745):397-8 [PMID: 6766207]
  83. Genes Dev. 2008 Nov 1;22(21):2953-67 [PMID: 18981474]
  84. Proc Natl Acad Sci U S A. 2002 May 14;99 Suppl 3:7280-7 [PMID: 12011407]
  85. Nat Rev Mol Cell Biol. 2006 Mar;7(3):165-76 [PMID: 16482094]
  86. FEBS Lett. 2010 Aug 4;584(15):3242-9 [PMID: 20542036]
  87. Genes Dev. 1999 Jan 1;13(1):20-5 [PMID: 9887096]
  88. Toxicology. 1998 Sep 15;130(2-3):79-93 [PMID: 9865476]
  89. Mol Cell. 2008 Mar 14;29(5):611-24 [PMID: 18342607]
  90. Mol Endocrinol. 2004 Jun;18(6):1411-27 [PMID: 15001666]
  91. Mol Cell Biol. 2010 Aug;30(16):3943-55 [PMID: 20547749]
  92. Toxicol Appl Pharmacol. 1995 Apr;131(2):253-66 [PMID: 7716767]
  93. Biochem Pharmacol. 1996 Oct 25;52(8):1147-54 [PMID: 8937421]
  94. J Toxicol Environ Health B Crit Rev. 2010 Feb;13(2-4):253-76 [PMID: 20574901]
  95. Cell. 2010 Mar 5;140(5):744-52 [PMID: 20211142]
  96. Hepatology. 1996 Nov;24(5):1296-311 [PMID: 8903413]
  97. Science. 2004 Feb 27;303(5662):1378-81 [PMID: 14988562]
  98. Wiley Interdiscip Rev Syst Biol Med. 2009 Sep-Oct;1(2):159-171 [PMID: 20835989]
  99. Arch Pharm Res. 2009 Feb;32(2):221-8 [PMID: 19280152]
  100. Arch Pharm Res. 2008 Apr;31(4):451-61 [PMID: 18449502]
  101. Theor Biol Med Model. 2008 May 27;5:11 [PMID: 18505587]
  102. Ann Intern Med. 2002 Dec 17;137(12):947-54 [PMID: 12484709]
  103. Immunol Res. 2006;36(1-3):237-45 [PMID: 17337784]
  104. Cancer Res. 1980 Oct;40(10):3616-20 [PMID: 6108157]
  105. Mol Cell Biol. 2010 Jan;30(1):231-44 [PMID: 19884340]
  106. Dev Biol. 2006 Jun 15;294(2):525-40 [PMID: 16626682]
  107. Cancer Res. 1996 Mar 15;56(6):1272-8 [PMID: 8640813]
  108. Carcinogenesis. 2010 Aug;31(8):1319-28 [PMID: 20106901]
  109. Mol Carcinog. 1989;1(4):216-21 [PMID: 2789688]
  110. J Pathol. 2000 Nov;192(3):373-8 [PMID: 11054721]
  111. Cell. 2005 Jul 15;122(1):33-43 [PMID: 16009131]
  112. Fundam Appl Toxicol. 1985 Feb;5(1):165-74 [PMID: 2859228]
  113. Science. 2005 Nov 11;310(5750):987-91 [PMID: 16284171]
  114. Mol Syst Biol. 2010 Sep 7;6:409 [PMID: 20823847]
  115. J Pharmacokinet Pharmacodyn. 2006 Dec;33(6):737-72 [PMID: 17051440]
  116. Cancer Cell. 2008 Mar;13(3):188-92 [PMID: 18328423]
  117. Arch Intern Med. 1981 Feb 23;141(3 Spec No):380-5 [PMID: 7469629]
  118. Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14806-11 [PMID: 14657377]
  119. Toxicol Lett. 1988 Jul;42(1):15-28 [PMID: 2838936]
  120. J Pharmacokinet Pharmacodyn. 2012 Oct;39(5):527-41 [PMID: 22875368]
  121. Nature. 2009 Nov 5;462(7269):58-64 [PMID: 19890323]
  122. Nucl Recept Signal. 2010 Apr 16;8:e002 [PMID: 20414453]
  123. PPAR Res. 2008;2008:134059 [PMID: 19125181]
  124. J R Soc Interface. 2007 Dec 22;4(17):1077-92 [PMID: 17374590]
  125. Biochim Biophys Acta. 2007 Aug;1771(8):972-82 [PMID: 17631413]
  126. Chem Res Toxicol. 2011 Apr 18;24(4):494-504 [PMID: 21370876]
  127. Mutat Res. 2007 Feb 3;615(1-2):87-97 [PMID: 17141280]
  128. BMC Syst Biol. 2008 Aug 18;2:75 [PMID: 18706112]
  129. Clin Chem. 1995 Dec;41(12 Pt 2):1829-34 [PMID: 7497640]
  130. Mech Dev. 2003 Jan;120(1):117-30 [PMID: 12490302]
  131. Bioinformatics. 2010 Sep 1;26(17):2169-75 [PMID: 20610613]
  132. Toxicology. 1995 Sep 1;102(1-2):223-37 [PMID: 7482557]
  133. Crit Care. 2009;13(3):144 [PMID: 19490595]
  134. Toxicol Appl Pharmacol. 2004 Apr 1;196(1):136-48 [PMID: 15050415]
  135. Curr Opin Chem Biol. 2006 Feb;10(1):20-7 [PMID: 16406766]
  136. J Pharmacol Exp Ther. 2004 Feb;308(2):694-704 [PMID: 14610242]
  137. Nat Immunol. 2007 May;8(5):441-4 [PMID: 17440447]
  138. Chem Biol Interact. 2000 Dec 15;129(3):279-95 [PMID: 11137066]
  139. Crit Care. 2009;13(2):R55 [PMID: 19358737]
  140. Genome Res. 2009 Dec;19(12):2163-71 [PMID: 19801529]
  141. Liver. 1998 Aug;18(4):288-93 [PMID: 9766827]
  142. Biochem Pharmacol. 2005 May 15;69(10):1403-8 [PMID: 15857604]
  143. PPAR Res. 2010;2010: [PMID: 20936127]
  144. Nat Cell Biol. 2006 Nov;8(11):1195-203 [PMID: 17060902]
  145. World J Gastroenterol. 2009 Feb 7;15(5):552-60 [PMID: 19195056]
  146. Annu Rev Cell Dev Biol. 1996;12:55-89 [PMID: 8970722]
  147. PLoS Comput Biol. 2009 Feb;5(2):e1000294 [PMID: 19247427]
  148. Curr Opin Cell Biol. 2003 Apr;15(2):221-31 [PMID: 12648679]
  149. Biophys J. 2006 May 15;90(10):3749-61 [PMID: 16500958]
  150. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1028-33 [PMID: 12552139]
  151. J Clin Invest. 2006 Mar;116(3):571-80 [PMID: 16511589]
  152. N Engl J Med. 2008 Jul 17;359(3):285-92 [PMID: 18635433]
  153. BMC Syst Biol. 2010 Apr 01;4:40 [PMID: 20359356]
  154. Mol Endocrinol. 2010 Dec;24(12):2392-405 [PMID: 20943813]
  155. Toxicology. 2007 Jan 5;229(1-2):62-72 [PMID: 17126469]
  156. Curr Opin Cell Biol. 2002 Apr;14(2):140-8 [PMID: 11891111]
  157. J Nutr Sci Vitaminol (Tokyo). 1998 Oct;44(5):613-24 [PMID: 9919482]
  158. Mol Pharmacol. 1996 Sep;50(3):538-48 [PMID: 8794892]

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