Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity

This report presents the definition and detailed documentation of chosen toxicological MoAs associated with repeated dose target organ toxicity as a first step in building a "prototype" safety assessment framework. In addition to providing a detailed description of the two chosen MoAs related to chronic liver toxicity, namely "MoA from Protein Alkylation to Liver Fibrosis" and "MoA from Liver X Receptor Activation to Liver Steatosis", the report also describes the working process leading to this result including the problems that have been encountered. The exercise followed as far as possible relevant WHO-IPCS and OECD guidance. The report represents the first deliverable of a contract of work between Cosmetics Europe and the European Commission's Joint Research Centre for supplementing the work of the SEURAT-1 research cluster.

[1]  G. Gores,et al.  Mechanisms of hepatotoxicity. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[2]  D. Brenner,et al.  Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis , 2007, Journal of gastroenterology and hepatology.

[3]  Jie Zhou,et al.  PXR and LXR in hepatic steatosis: a new dog and an old dog with new tricks. , 2008, Molecular pharmaceutics.

[4]  Gregor Eichele,et al.  9-cis retinoic acid is a high affinity ligand for the retinoid X receptor , 1992, Cell.

[5]  L Zhang,et al.  Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. , 1994, Journal of medicinal chemistry.

[6]  M. Pinzani,et al.  Liver fibrosis: from the bench to clinical targets. , 2004, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[7]  R. Andrade,et al.  Drug-induced hepatotoxicity , 2003, The New England journal of medicine.

[8]  R. Hammer,et al.  Diminished Hepatic Response to Fasting/Refeeding and Liver X Receptor Agonists in Mice with Selective Deficiency of Sterol Regulatory Element-binding Protein-1c* , 2002, The Journal of Biological Chemistry.

[9]  D. Ory.  Nuclear receptor signaling in the control of cholesterol homeostasis: have the orphans found a home? , 2004, Circulation research.

[10]  D. Mangelsdorf,et al.  Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. , 2000, Science.

[11]  J. Iredale,et al.  Liver fibrosis: cellular mechanisms of progression and resolution. , 2007, Clinical science.

[12]  S. Kakar,et al.  Histological patterns in drug-induced liver disease , 2009, Journal of Clinical Pathology.

[13]  B. Spiegelman,et al.  ADD1/SREBP-1c Is Required in the Activation of Hepatic Lipogenic Gene Expression by Glucose , 1999, Molecular and Cellular Biology.

[14]  J. Cha,et al.  The Liver X Receptor (LXR) and Hepatic Lipogenesis , 2007, Journal of Biological Chemistry.

[15]  D. Brenner,et al.  Erratum: Liver fibrosis (Journal of Clinical Investigation (2005) 115 (209-218) DOI:10.1172/JCI200524282) , 2005 .

[16]  N. Nowak,et al.  Lipid in the livers of adolescents with nonalcoholic steatohepatitis: combined effects of pathways on steatosis. , 2011, Metabolism: clinical and experimental.

[17]  Alan R. Boobis,et al.  IPCS Framework for Analyzing the Relevance of a Cancer Mode of Action for Humans , 2006 .

[18]  A. Das,et al.  Fibrosis, chronic inflammation and new pathways for drug discovery , 2008, Inflammation Research.

[19]  W. Stremmel,et al.  Uptake of long chain fatty acids is regulated by dynamic interaction of FAT/CD36 with cholesterol/sphingolipid enriched microdomains (lipid rafts) , 2008, BMC Cell Biology.

[20]  Bethany Croke,et al.  Nonalcoholic Fatty Liver Disease: Implications for Clinical Practice and Health Promotion , 2012 .

[21]  G. Robino,et al.  Oxidative stress-related molecules and liver fibrosis. , 2001, Journal of hepatology.

[22]  K. Højlund,et al.  Liver X receptor antagonist reduces lipid formation and increases glucose metabolism in myotubes from lean, obese and type 2 diabetic individuals , 2007, Diabetologia.

[23]  J. Iredale.  Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. , 2007, The Journal of clinical investigation.

[24]  J. Girard,et al.  Sterol regulatory element binding protein-1c expression and action in rat muscles: insulin-like effects on the control of glycolytic and lipogenic enzymes and UCP3 gene expression. , 2002, Diabetes.

[25]  R. Hammer,et al.  Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα , 1998, Cell.

[26]  B. Aggarwal,et al.  Oxidative stress, inflammation, and cancer: how are they linked? , 2010, Free radical biology & medicine.

[27]  G. Poli.  Pathogenesis of liver fibrosis: role of oxidative stress. , 2000, Molecular aspects of medicine.

[28]  Angela M. Siesky,et al.  Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha. , 2005, Endocrinology.

[29]  Pascale Bossard,et al.  ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. , 2008, The Journal of clinical investigation.

[30]  Suzhen Li,et al.  Induction of Human Liver X Receptor α Gene Expression Via an Autoregulatory Loop Mechanism , 2002 .

[31]  D. Averill-Bates,et al.  Activation of the death receptor pathway of apoptosis by the aldehyde acrolein. , 2007, Free radical biology & medicine.

[32]  V. Christiaens,et al.  CD36 promotes adipocyte differentiation and adipogenesis. , 2012, Biochimica et biophysica acta.

[33]  Hartmut Jaeschke,et al.  Apoptosis and necrosis in liver disease , 2004, Liver international : official journal of the International Association for the Study of the Liver.

[34]  A. Staiano,et al.  Ethnic and sex differences in body fat and visceral and subcutaneous adiposity in children and adolescents , 2012, International Journal of Obesity.

[35]  M. Foretz,et al.  Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Friedman.  Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury* , 2000, The Journal of Biological Chemistry.

[37]  D. Eastmond,et al.  Postulated Carbon Tetrachloride Mode of Action: A Review , 2007, Journal of environmental science and health. Part C, Environmental carcinogenesis & ecotoxicology reviews.

[38]  D. Brenner.  Molecular pathogenesis of liver fibrosis. , 2009, Transactions of the American Clinical and Climatological Association.

[39]  J. Iredale,et al.  Modeling liver fibrosis in rodents. , 2005, Methods in molecular medicine.

[40]  S. Friedman,et al.  Mechanisms of hepatic fibrogenesis. , 2008, Gastroenterology.

[41]  H. Wasmuth,et al.  Liver fibrosis: from animal models to mapping of human risk variants. , 2010, Best practice & research. Clinical gastroenterology.

[42]  D. Mangelsdorf,et al.  The role of liver X receptor-alpha in the fatty acid regulation of hepatic gene expression. , 2003, The Journal of biological chemistry.

[43]  Joseph L Goldstein,et al.  SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. , 2002, The Journal of clinical investigation.

[44]  D. Mangelsdorf,et al.  Role of LXRs in control of lipogenesis. , 2000, Genes & development.

[45]  L. Mitnaul,et al.  Different roles of liver X receptor alpha and beta in lipid metabolism: effects of an alpha-selective and a dual agonist in mice deficient in each subtype. , 2006, Biochemical pharmacology.

[46]  P. Bioulac-Sage,et al.  [Mechanisms of hepatic fibrogenesis]. , 2002, Archives de pediatrie : organe officiel de la Societe francaise de pediatrie.

[47]  J. González‐Gallego,et al.  Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C , 2011, Gut.

[48]  X. Su,et al.  Cellular fatty acid uptake: a pathway under construction , 2009, Trends in Endocrinology & Metabolism.

[49]  C. Day,et al.  Treatment of Non-Alcoholic Fatty Liver Disease , 2014, Digestive Diseases.

[50]  L. Moore,et al.  Williams, S. et al. X-ray crystal structure of the liver X receptor ligand binding domain: regulation by a histidine-tryptophan switch. J. Biol. Chem. 278, 27138-27143 , 2003 .

[51]  C. Day,et al.  Steatohepatitis: a tale of two "hits"? , 1998, Gastroenterology.

[52]  James Q. Yin,et al.  Therapeutic strategies against TGF‐β signaling pathway in hepatic fibrosis , 2006 .

[53]  Suzhen Li,et al.  Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism. , 2002, Molecular endocrinology.

[54]  J. Odeberg,et al.  Hormonal and nutritional regulation of alternative CD36 transcripts in rat liver – a role for growth hormone in alternative exon usage , 2007, BMC Molecular Biology.

[55]  M. Miyazaki,et al.  Stearoyl-Coenzyme A Desaturase 1 Deficiency Protects against Hypertriglyceridemia and Increases Plasma High-Density Lipoprotein Cholesterol Induced by Liver X Receptor Activation , 2006, Molecular and Cellular Biology.

[56]  T. Willson,et al.  Liver X Receptor (LXR) Regulation of the LXRα Gene in Human Macrophages* , 2001, The Journal of Biological Chemistry.

[57]  R. Ravi,et al.  Effects of acetaldehyde and TNFα on the inhibitory kappa B- α protein and nuclear factor kappa B activation in hepatic stellate cells , 2005 .

[58]  H. Tsukamoto,et al.  Experimental Models of Hepatic Fibrosis: A Review , 1990, Seminars in liver disease.

[59]  N. Mitro,et al.  T0901317 is a potent PXR ligand: Implications for the biology ascribed to LXR , 2007, FEBS letters.

[60]  S. Friedman,et al.  Hepatic fibrosis--role of hepatic stellate cell activation. , 2002, MedGenMed : Medscape general medicine.

[61]  P. Kirkham.  Oxidative stress and macrophage function: a failure to resolve the inflammatory response. , 2007, Biochemical Society transactions.

[62]  N. Abumrad,et al.  CD36 genetics and the metabolic complications of obesity , 2011, Current opinion in clinical nutrition and metabolic care.

[63]  H. Jaeschke.  Inflammation in response to hepatocellular apoptosis , 2002 .

[64]  F. Foufelle,et al.  Hepatic steatosis: a role for de novo lipogenesis and the transcription factor SREBP‐1c , 2010, Diabetes, obesity & metabolism.

[65]  T. Vanhaecke,et al.  Screening of repeated dose toxicity data present in SCC(NF)P/SCCS safety evaluations of cosmetic ingredients , 2012, Archives of Toxicology.

[66]  R. Silverstein,et al.  A Null Mutation in Murine CD36 Reveals an Important Role in Fatty Acid and Lipoprotein Metabolism* , 1999, The Journal of Biological Chemistry.

[67]  D. Kershenobich Stalnikowitz,et al.  Liver fibrosis and inflammation. A review. , 2003, Annals of hepatology.

[68]  A. Mallat,et al.  Hepatic fibrosis: molecular mechanisms and drug targets. , 2005, Annual review of pharmacology and toxicology.

[69]  Scott L. Friedman,et al.  Evolving challenges in hepatic fibrosis , 2010, Nature Reviews Gastroenterology &Hepatology.

[70]  Timothy M Willson,et al.  Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. , 2002, Journal of medicinal chemistry.

[71]  S. Biswal,et al.  The molecular effects of acrolein. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[72]  Daniel C Liebler,et al.  Protein damage by reactive electrophiles: targets and consequences. , 2008, Chemical research in toxicology.

[73]  J. Castell,et al.  Enhanced steatosis by nuclear receptor ligands: a study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile. , 2010, Chemico-biological interactions.

[74]  F. Foufelle,et al.  SREBP-1c Transcription Factor and Lipid Homeostasis: Clinical Perspective , 2007, Hormone Research in Paediatrics.

[75]  A. Kahraman,et al.  Apoptosis is associated with CD36/fatty acid translocase upregulation in non‐alcoholic steatohepatitis , 2009, Liver international : official journal of the International Association for the Study of the Liver.

[76]  Qiu Guo,et al.  Different roles of liver X receptor α and β in lipid metabolism: Effects of an α-selective and a dual agonist in mice deficient in each subtype , 2006 .

[77]  Youhua Liu.  Cellular and molecular mechanisms of renal fibrosis , 2011, Nature Reviews Nephrology.

[78]  F. Foufelle,et al.  SREBP transcription factors: master regulators of lipid homeostasis. , 2004, Biochimie.

[79]  Albert K Groen,et al.  The liver X receptor: control of cellular lipid homeostasis and beyond Implications for drug design. , 2010, Progress in lipid research.

[80]  C. Mantzoros,et al.  The emerging role of endocrine disruptors in pathogenesis of insulin resistance: a concept implicating nonalcoholic fatty liver disease. , 2012, Current molecular medicine.

[81]  M. Febbraio,et al.  The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease , 2011, Experimental biology and medicine.

[82]  G. Gores,et al.  Apoptosis: The nexus of liver injury and fibrosis , 2004, Hepatology.

[83]  T. Willson,et al.  Sweet dreams for LXR. , 2007, Cell metabolism.

[84]  P. Edwards,et al.  LXRs; oxysterol-activated nuclear receptors that regulate genes controlling lipid homeostasis. , 2002, Vascular pharmacology.

[85]  Katsumi Iizuka,et al.  Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[86]  N. Chalasani,et al.  Risk Factors for Drug-Induced Liver Disease , 2013 .

[87]  M. Laville,et al.  Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. , 2001, Diabetes.

[88]  T. Wynn,et al.  Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. , 2007, The Journal of clinical investigation.

[89]  T. Willson,et al.  Liver X receptor (LXR) regulation of the LXRalpha gene in human macrophages. , 2001, The Journal of biological chemistry.

[90]  J. Bełtowski,et al.  Liver X receptors (LXRs). Part II: non-lipid effects, role in pathology, and therapeutic implications. , 2007, Postepy higieny i medycyny doswiadczalnej.

[91]  Ignazio Grattagliano,et al.  Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity , 2009, Current medicinal chemistry.

[92]  H. Shimano,et al.  Sterol Regulatory Element-binding Protein-1 as a Key Transcription Factor for Nutritional Induction of Lipogenic Enzyme Genes* , 1999, The Journal of Biological Chemistry.

[93]  Jie Zhou,et al.  Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. , 2008, Gastroenterology.

[94]  L. Weber,et al.  Mechanism of Carbon Tetrachloride-Induced Hepatotoxicity. Hepatocellular Damage by Reactive Carbon Tetrachloride Metabolites , 2001, Zeitschrift fur Naturforschung. C, Journal of biosciences.

[95]  W. Stremmel,et al.  Overexpression of CD36 and Acyl-CoA Synthetases FATP2, FATP4 and ACSL1 Increases Fatty Acid Uptake in Human Hepatoma Cells , 2011, International journal of medical sciences.

[96]  J. Girard,et al.  Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. , 2008, The Journal of clinical investigation.

[97]  D. Amacher.  The mechanistic basis for the induction of hepatic steatosis by xenobiotics , 2011, Expert opinion on drug metabolism & toxicology.

[98]  D. Mangelsdorf,et al.  Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[99]  D. Mangelsdorf,et al.  The Role of Liver X Receptor-α in the Fatty Acid Regulation of Hepatic Gene Expression* , 2003, Journal of Biological Chemistry.

[100]  B. Fromenty,et al.  Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. , 2011, Journal of hepatology.

[101]  M. Válková.  Hepatic fibrogenesis. , 2002, Bratislavske lekarske listy.

[102]  M. Jaye,et al.  Synthetic LXR agonists increase LDL in CETP species Published, JLR Papers in Press, July 16, 2005. DOI 10.1194/jlr.M500116-JLR200 , 2005, Journal of Lipid Research.

[103]  W. Stremmel,et al.  FAT/CD36-mediated long-chain fatty acid uptake in adipocytes requires plasma membrane rafts. , 2004, Molecular biology of the cell.

[104]  D. Brenner,et al.  Mechanisms of Fibrogenesis , 2008, Experimental biology and medicine.

[105]  B. Zhivotovsky,et al.  Cell death mechanisms and their implications in toxicology. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[106]  C. Chatziantoniou,et al.  Insights into the mechanisms of renal fibrosis: is it possible to achieve regression? , 2005, American journal of physiology. Renal physiology.

[107]  Angela M. Siesky,et al.  Hepatic peroxisomal fatty acid β-oxidation is regulated by liver X receptor α , 2005 .

[108]  M. Beylot,et al.  Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification. , 1998, American journal of physiology. Endocrinology and metabolism.

[109]  G. Gores,et al.  Hepatocyte death: a clear and present danger. , 2010, Physiological reviews.

[110]  D. Pessayre,et al.  Hepatotoxicity due to mitochondrial dysfunction , 2004, Cell Biology and Toxicology.

[111]  J. Olefsky,et al.  Nuclear Receptor Minireview Series* , 2001, The Journal of Biological Chemistry.

[112]  G. Labbe,et al.  Drug‐induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies , 2008, Fundamental & clinical pharmacology.

[113]  S. Dooley,et al.  Roles of TGF-beta in hepatic fibrosis. , 2002, Frontiers in bioscience : a journal and virtual library.

[114]  M. Pfahl,et al.  A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily , 1994, Molecular and cellular biology.

[115]  T. Wynn,et al.  Cellular and molecular mechanisms of fibrosis , 2008, The Journal of pathology.

[116]  J. Olsen,et al.  The European Commission , 2020, The European Union.

[117]  R. Hiipakka,et al.  Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[118]  R. Walczak,et al.  Autoregulation of the Human Liver X Receptor α Promoter , 2001, Molecular and Cellular Biology.

[119]  J. Gustafsson,et al.  Physiological Differences between Human and Rat Primary Hepatocytes in Response to Liver X Receptor Activation by 3-[3-[N-(2-Chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic Acid Hydrochloride (GW3965) , 2007, Molecular Pharmacology.

[120]  Janardan K Reddy,et al.  Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. , 2006, American journal of physiology. Gastrointestinal and liver physiology.

[121]  D. Azzout-Marniche,et al.  Adenovirus-mediated overexpression of sterol regulatory element binding protein-1c mimics insulin effects on hepatic gene expression and glucose homeostasis in diabetic mice. , 2001, Diabetes.

[122]  Jan G. Hengstler,et al.  Highlight report: towards the replacement of in vivo repeated dose systemic toxicity testing , 2011, Archives of Toxicology.

[123]  M. Boehm,et al.  Design and synthesis of potent retinoid X receptor selective ligands that induce apoptosis in leukemia cells. , 1995, Journal of medicinal chemistry.

[124]  I. Shimomura,et al.  Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. , 1997, The Journal of clinical investigation.

[125]  D. Pessayre,et al.  Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines. , 1997, Journal of hepatology.

[126]  M. Baranowski,et al.  Biological role of liver X receptors. , 2008, Journal of physiology and pharmacology : an official journal of the Polish Physiological Society.

[127]  D. Kershenobich,et al.  Hepatic Fibrosis , 1955, Gastroenterology.

[128]  G. Kolios,et al.  Role of Kupffer cells in the pathogenesis of liver disease. , 2006, World journal of gastroenterology.