Alternatives in Testing for Hepatotoxicity

  • Fabienne Goethals
  • Marcel Roberfroid
Part of the NATO ASI Series book series (volume 93)


Toxicology studies the properties of chemicals and their effects on living organisms with the aim to assess their potential adverse effects so as to help preserve and protect human health.


Valproic Acid Glycogen Content Liver Slice Sodium Valproate Microvesicular Steatosis 
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  1. Balls M., Blaauboer B., Brusick D., Frazier J., Lamb D., Pemberton M., Reinhardt C., Roberfroid M., Rosenkranz H., Schmid B., Spielman H., Stammati A.L. and Walum E. (1990) Report and recommandations of an international workshop on promotion of the regulatory acceptance of validated non-animal toxicity test procedures. ATLA, 18: 317–337.Google Scholar
  2. Becker C.M. and Harris R.A. (1983) Influence of valproic acid on hepatic carbohydrate and lipid metabolism. Arch. Biochem. Biophys., 22: 381–392CrossRefGoogle Scholar
  3. Blaude M.N., Goethals F.M., Ansay M.A. and Roberfroid M.B. (1990) Interaction between aflatoxin B1 and oxytetracycline in isolated rat hepatocytes. Cell. Biol. Toxicol., 6: 339–351PubMedCrossRefGoogle Scholar
  4. Blaude M.N., Goethals F.M., Ansay M.A., and Roberfroid M.B. (1992) Synergism between aflatoxin B1 and oxytetracycline on fatty acid esterification in isolated rat hepatocytes. Toxicol. Lett., 61: 159–166PubMedCrossRefGoogle Scholar
  5. Brendel K., Gandolfi A.J., Krumdieck C.L. and Smith P.F. (1987) Tissue slicing and culturing revisited. Trends Pharm. Sci., 8: 11–15CrossRefGoogle Scholar
  6. Clifford J.I. and Rees K.R. (1967) The action of aflatoxin Bi on the rat liver. Biochem. J., 102: 65–75PubMedGoogle Scholar
  7. Connors S., Rankin D.R., Gandolfi A.J., Krumdieck C.L., Koep L.J. and Brendel K. (1990) Cocaine hepatotoxicity in cultured liver slices: a species comparison. Toxicology, 61: 171–183PubMedCrossRefGoogle Scholar
  8. Coudé F.X., Grimber G., Pelet A., Benoit Y. (1983) Action of the antiepileptic drug, valproic acid on fatty acid oxidation in isolated rat hepatocytes. Biochem. Biophys. Res. Commun., 115: 730–736PubMedCrossRefGoogle Scholar
  9. Deboyser D., Goethals F., Krack G. and Roberfroid M. (1989) Investigation into the mechanism of tetracycline-induced steatosis: study in isolated hepatocytes. Toxicol. Appl. Pharmacol., 97: 473–479PubMedCrossRefGoogle Scholar
  10. Dogterom P. (1993) Development of a simple incubation system for metabolism studies with precision-cut liver slices. Drug Metab. Disp., 21: 699–704Google Scholar
  11. Dogterom P. and Rothuizen J. (1993) A species comparison of tolbutamide metabolism in precision-cut liver slices from rats and dogs. Qualitative and quantitative sex differences. Drug. Metab. Disp., 21: 705–709Google Scholar
  12. Fischer R., Barr J., Zukoski C.F., Putnam C.W., Sipes I.G., Gandolfi A.J. and Brendel K. (1991b) In vitro hepatotoxicity of three dichlorobenzene isomers in human liver slices. Human Exp. Toxicol., 10: 357–363Google Scholar
  13. Fischer R., Nau H., Gandolfi A.J. and Brendel K. (1991a) Toxicity of valproic acid in liver slices from Sprague-Dawley rats and domestic pigs. Toxicol, in Vitro, 5: 201–205CrossRefGoogle Scholar
  14. Fischer R., Nau, H., Gandolfi A.J., Putnam C.W. and Brendel K. (1991c) Valproic acid hepatotoxicity in human liver slices. Drug. Chem. Toxicol., 14: 375–394CrossRefGoogle Scholar
  15. Goethals F., Deboyser D., Lefebvre V., Decoster I. and Roberfroid M. (1990) Adult rat liver slices as a model for studying the hepatotoxicity of vincaalkaloids. Toxicol, in Vitro., 4: 435–438CrossRefGoogle Scholar
  16. Gravela E., Poli G., Albano E. and Dianzani M. (1977) Study on fatty liver with isolated hepatocytes. I. The action of colchicine, phalloidin, cytochalasin B and cycloheximide on protein and triglyceride synthesis and secretion. Exp. Mol. Pathol., 27: 339–352CrossRefGoogle Scholar
  17. Gunawardhara L., Barr J., Weir A.J., Brendel K. and Sipes I.J. (1991) The N-acetylation of sulfamethazine and p-aminobenzoic acid by human liver slices in dynamic organ culture. Drug. Metab. Disp., 19: 648–654Google Scholar
  18. Kroes R. and Hicks M. (1990) Introduction. Réévaluation of current methodology of toxicology testing including gross nutrients. Proceedings of a symposium held on 5–7 April 1989, Chateau de Limelette, Belgium. Food and Chem. Toxicol., 28: 733–734Google Scholar
  19. Krumdieck C.L., Dos Santos J.E. and Ho K.J. (1980) A new instrument for the rapid preparation of tissue slices. Anal. Biochem., 104: 118–123PubMedCrossRefGoogle Scholar
  20. Lake B.G., Beamand J.A., Japenga A.C., Renwick A., Davies S. and Price R.J. (1993) Induction of cytochrome P450-dependent enzyme activities in cultured rat liver slices. Fd. Chem. Toxicol., 31: 377–386Google Scholar
  21. Le Marchand Y., Singh A., Assimacopoulos-Jeannet F., Orci L., Rouiller C. and Jeanrenaud B. (1973) A role for the microtubular system in the release of very low density lipoproteins by perfused mouse livers. J. Biol. Chem., 248: 6862–6870PubMedGoogle Scholar
  22. Phelps J.S., Gandolfi A.J., Brendel K. and Dorr R.T. (1987) Cisplatin nephrotoxicity: in vitro studies with precision-cut rabbit renal slices. Toxciol. Appl. Pharmacol., 90: 501–512CrossRefGoogle Scholar
  23. Ruegg C.E., Gandolfi A.J., Nagle R.B. and Brendel K. (1987) Differential patterns of injury to the proximal tubule of renal cortical slices ¡following in vitro exposure to mercuric chloride, potassium dichromate or hypoxic conditions. Toxicol. Appl. Pharmacol., 90: 261–273PubMedCrossRefGoogle Scholar
  24. Ruegg C.E., Grushenka H.I., Wolfgang G.H., Gandolfi A.J., Brendel K. and Krumdieck C.L. (1989) Preparation and utilization of positional renal slices for in vitro nephrotoxicity studies. In: In vitro Toxicology: Model Systems and Methods ( Ch.A. Mc Queen, ed), 197–230, The Telford Press Inc., New JerseyGoogle Scholar
  25. Roberfroid M. (1991) Long term policy in toxicology. In: animals in Biochemical Research (H. Koeter and Ph. Anderson, eds),pp 35–48, Elsevier Sci. Publ., New York, LondonGoogle Scholar
  26. Roberfroid M. and Goethals F. (1990), In vitro toxicology: a challenge for the 21st century. ATLA, 18: 19–22Google Scholar
  27. Roberfroid M. and Goethals F. (1992) In vitro toxico-pharmacology: past, present and future. In: In vitro Alternatives to Animal Pharmaco-Toxicology ( J.V. Casterll and M.J. Gomez-Lechon, eds), pp 17–41, Farmaindustria, MadridGoogle Scholar
  28. Rodricks J.V. (1986) Improving the use of risk assessment in regulation. Comments on Toxicol., 1: 75–96Google Scholar
  29. Smith P.F., Gandolfi A.J., Krumdieck C.L., Putnam C.W., Zukoski C.F., Davis W.M. and Brendel K. (1985) Dynamic organ culture of precision cut liver slices for in vitro toxicology. Life Sci., 36: 1367–1375PubMedCrossRefGoogle Scholar
  30. Smith P.F., Krack G., McKee R.L., Johnson D.G., Gandolfi A.J., Hruby V.J., Krumdieck C.L. and Brendel K. (1986) Maintenance of adult rat liver slices in dynamic organ culture. In vitro Cell Develop. Biol., 22: 706–712CrossRefGoogle Scholar
  31. Stearns R.A., Miller R.R., Doss G.A., Chakravarty P.K., Rosegay A., Gatto G.J. and Chiu S.H.L. (1992) The metabolism of DuP753, a nonpeptide angiotensin II receptor antagonist, by rat, monkey, and human liver slices. Drug. Metab. Disp. 20: 281–287Google Scholar
  32. Stefaniak M.S., Gandolfi A.J. and Brendel K. (1988) Adult rat lung slices in dynamic organ culture: a new tool in pharmacology. Proc. West. Pharmacol. Soc., 31: 149–151Google Scholar
  33. Stein O. and Stein Y. (1973) Colchicine-induced inhibition of very low density lipoprotein release by rat liver in vivo. Biochim. Biophys. Acta, 306: 142–147PubMedGoogle Scholar
  34. Strieker B.H. and Spoelstra P. (1985) Tetracyclines. In: Drug-Induced Hepatic Injury ( M.N.G. Dukers, ed), p 157, Elsevier, Amsterdam.Google Scholar
  35. Turnbull D.M., Bone A.S., Bartlett K., Koundakjian P.P. and Sheratt H.S.A. (1983) The effects of valproate on intermediary metabolism in isolated rat hepatocytes and intact rats. Biochem. Pharmacol., 32: 1887–1892Google Scholar
  36. Vickers A.E.M., Fisher V., Connors S., Fischer R.L., Baldeck J.P., Maurer G. and Brendel K. (1992) Cyclosporin A metabolism in human liver, kidney, and intestine slices. Comparison to rat and dog slices and human cell lines. Drug. Metab. Disp. 20: 802–809Google Scholar
  37. Wolfgang G.H.I., Donarski W.J. and Petry T.W. (1990) Effects of novel antioxidants on carbon tetrachloride induced lipid peroxidation and toxicity in precision cut rat liver slices. Toxicol. Appl. Pharmacol., 106: 63–70PubMedCrossRefGoogle Scholar
  38. Wright M.C. and Paine A.J. (1992) Evidence that the loss of rat liver cytochrome P450 in vitro is not solely associated with the use of collagenase, the loss of cell-cell contacts and/or the absence of an extracellular matrix. Biochem. Pharmacol., 43: 237–243PubMedCrossRefGoogle Scholar
  39. Zimmerman H.S. (1979) Drug-induced chronic hepatic disease. Med. Clin. North Amer, 63: 567–582Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • Fabienne Goethals
    • 1
  • Marcel Roberfroid
    • 1
  1. 1.Unité de Biochimie Toxicologique et Cancérologique, Departement des Sciences PharmaceutiquesUniversité Catholique de LouvainBrusselsBelgium

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