Isolated hepatocyte systems are being examined in our laboratory for a number of applications, including alternatives to animal test ing. This report summarizes findings from studies with chlorinated aliphatics, acetaminophen, nitrotoluenes, and cyanide and its anti dotes that relate to in vivo toxicity and validation of these systems for cytotoxicity screening.
Acosta, D., Anufuro, D. and Smith, R.V. (1980). Cytotoxicity of acetaminophen and papaverine in primary cultures of rat hepatocytes. Toxicol. Appl. Pharmacol.53:306-314.
2.
Acosta, D., Sorensen, E.M.B., Anuforo, D.C., Mitchell, D.B., Ramos, K., Santone, K.S. and Smith, M.A. (1985). An in vitro approach to the study of drugs and chemicals. In Vitro Cell. Dev. Biol.21:495-504.
3.
Albano, E., Poli, G., Chiarpotto, E., Biasi, F. and Dianzani, M.U. (1983). Paracetamol-stimulated lipid peroxidation in isolated rat and mouse hepatocytes. Chem.-Biol. Interact.47:249-263.
4.
Aune, T. and Berg, K. (1986). Use of freshly prepared rat hepatocytes to study toxicity of blooms of the blue-green algae Microcystis aeruginosa and Oscillatoria agardhii. J. Toxicol. Environ. Health19:325-336.
5.
Becker, R.A. and Reid, J.B. (1987). Carcinogenic and Toxicologic Bioassay of Various Chemicals. 14-Day Repeated-Exposure Toxicology Investigation of Sodium Cyanide Administered to Male and Female F-344 Rats in Drinking Water. NIH Contract ES-65154. SRI International, Menlo Park, CA. February.
6.
Black, M. (1980). Acetaminophen hepatotoxicity. Gastroenterology78:382-392.
7.
Boobis, A.R., Tee, L.B.G., Hampden, C.E. and Davies, D.S. (1986). Freshly isolated hepatocytes as a model for studying the toxicity of paracetamol. Food Chem. Toxicol.24:731-736.
8.
Bridges, J.W., Benford, D.J. and Hubbard, S.A. (1983). Mechanisms of toxic injury. Ann. NY Acad. Sci.407:42-63.
9.
Briggs, M. and Briggs, M. (1974). Chemistry and Metabolism of Drugs and Toxins: An Introduction to Xenobiochemistry. W. Heinemann Medical Books, Ltd., London.
10.
Cantilena, L.R., Stacey, N.H. and Klaassen, C.D. (1983). Isolated rat hepatocytes as a model system for screening chelators for use in cadmium intoxication. Toxicol. Appl. Pharmacol.67:257-263.
11.
Cheng, L.Y. and Ji, S. (1984). Inhibition of mitochondrial respiration by acetaminophen: a new mechanism of acetaminophen hepatotoxicity. The Toxicologist4:78.
12.
Davis, D.C., Potter, W.Z., Jollow, D.J. and Mitchell, J.R. (1974). Species differences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen. Life Sci.14:2099-2109.
13.
Dewar, M.F.S. and Thiel, W. (1977). Ground states of molecules. XXXIX. MNDO results for molecules containing hydrogen, carbon, nitrogen, and oxygen. J. Am. Chem. Soc.99:4907-4917.
14.
Dilley, J.V., Tyson, C.A., Spanggord, R.J., Sasmore, D.P., Newell, G.W. and Dacre, J.C. (1982). Short-term oral toxicity of 2,4,6-trinitrotoluene in mice, rats, and dogs. J. Toxicol. Environ. Health9:565-585.
15.
Ekwall, B. (1980). Screening of toxic compounds in tissue culture . Toxicology17:127-142.
16.
Ekwall, B. and Acosta, D. (1982). In vitro comparative toxicity of selected drugs and chemicals in HeLa cells, Chang liver cells, and rat hepatocytes. Drug Chem. Toxicol.5:219-231.
17.
Farland, W.H., Tyson, C.A. and Sawhney, D.S. (1985). Rationale and use of functions tests in toxicity testing: a review. In: Organ Function Tests in Toxicity Evaluation . C.A. Tyson and D.S. Sawhney, eds., pp. 1-22. Noyes Publications, Park Ridge, NJ.
18.
Flanagan, R.J. and Mant, T.G.K. (1986). Coma and metabolic acidosis early in severe acute paracetamol poisoning. Hum. Toxicol.5:179-182.
19.
Frankenberg, L. and Sorbo, B. (1975). Effect of cyanide antidotes on the metabolic conversion of cyanide to thiocyanate. Arch. Toxicol.33:81-89.
20.
Fry, J.R. and Bridges, J.W. (1976). The metabolism of xenobiotics in cell suspensions and cell cultures. Prog. Drug Metab.2:71-118.
21.
Fry, J.R. and Bridges, J.W. (1979). Use of primary hepatocyte cultures in biochemical toxicology. In: Reviews in Biochemical Toxicology. Vol. 1, pp. 201-247. E. Hodgson, J.R. Bend, and R.M. Philpot eds., Elsevier North Holland, Amsterdam.
22.
Gee, S.J., Green, C.E. and Tyson, C.A. (1984). Comparative tolbutamide metabolism in isolated hepatocytes from rat, rabbit, dog, and squirrel monkey. Drug Metab. Dispos.12:174-178.
23.
Gee, S.J., Le Valley, S.E. and Tyson, C.A. (1987). Application of a hepatocyte-erythrocyte coincubation system to studies of cyanide antidotal mechanisms. Toxicol. Appl. Pharmacol.88:24-34.
24.
Gerson, R.J., Casini, A., Gilfor, D., Serroni, A. and Farber, J.L. (1985). Oxygen-mediated cell injury in the killing of cultured hepatocytes by acetaminophen. Biochem. Biophys. Res. Commun.126:1129-1137.
25.
Gillette, J.B. (1974). A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity - I. Correlation of changes in covalent binding of reactivity metabolites with changes in the incidence and severity of toxicity. Biochem. Pharmacol.23:2785-2794.
26.
Goethals, F., Krack, G., Deboyser, D., Vossen, P. and Roberfroid, M. (1984). Critical biochemical functions of isolated hepatocytes as sensitive indicators of chemical toxicity. Fundam. Appl. Toxicol.4:441-450.
27.
Goldberg, A.M. (1983). Alternative Methods in Toxicology. Product Safety Evaluation. Mary Ann Liebert Publishers, New York.
28.
Gottschall, D.W., Wiley, R.A. and Hanzlik, R.P. (1983). Toxicity of ortho-substituted bromobenzenes to isolated hepatocytes: comparison to in vivo results. Toxicol. Appl. Pharmacol.69:55-65.
29.
Gray, T.J., Lake, B.G., Beamand, J.A., Foster, J.R. and Gangolli, S.D. (1983). Peroxisome proliferation in primary cultures of rat hepatocytes. Toxicol. Appl. Pharmacol.67:15-25.
30.
Green, C.E., Dabbs, J.E. and Tyson, C.A. (1983). Functional integrity of isolated rat hepatocytes prepared by whole liver vs. biopsy perfusion. Anal. Biochem.129:269-276.
31.
Green, C.E., Dabbs, J.E. and Tyson, C.A. (1984). Metabolism and cytotoxicity of acetaminophen in hepatocytes isolated from resistant and susceptible species. Toxicol. Appl. Pharmacol.76:139-149.
32.
Green, C.E., Le Valley, S.E. and Tyson, C.A. (1986). Comparison of amphetamine metabolism using isolated hepatocytes from 5 species including humans. J. Pharmacol. Exp. Therap.237:931-936.
33.
Green, C.E., Hanko, V.P., Gordon, G.R., Peters, J.H. and Tyson, C.A. (1987). Acetylation/deacetylation (AC/DC) of aryl amines in human and rat liver. The Toxicologist7:220.
34.
Guillouzo, A. and Guguen-Guillouzo, C. (1986). Isolated and Cultured Hepatocytes. John Libbey & Co., London.
35.
Haseman, J.K., Crawford, D.D., Huff, J.E., Boorman, G.A. and Mccon-Nell, E.E. (1984). Results from 86 two-year carcinogenicity studies conducted by the National Toxicology Program. J. Toxicol. Environ. Health14:621-639.
36.
Hanzlik, R.P., Gillesse, T.J. and Wiley, R.A. (1982). Toxicity and covalent binding of substituted bromobenzenes to isolated hepatocytes. Adv. Exp. Med. Biol.136A:381-386.
37.
Hinson, J.A., Pohl, L.R., Monks, T.J. and Gillette, J.R. (1981). Minireview. Acetaminophen-induced hepatotoxicity . Life Sci.29:107-116.
38.
Holme, J.A. and Soderlund, E. (1986). Species differences in cytotoxic and genotoxic effects of phenacetin and paracetamol in primary monolayer cultures of hepatocytes . Mutat. Res.164:167-175.
39.
Inmon, J., Stead, A., Water, M.D. and Lewtas, J. (1981). Development of a toxicity test system using primary rat liver cells. In Vitro17:1004-1010.
40.
Isom, G. and Way, J.L. (1973). Cyanide intoxication, protection with cobaltous chloride. Toxicol. Appl. Pharmacol.24:449-456.
41.
Jollow, D.J., Mitchell, J.R., Potter, W.Z., Davis, D.C., Gillette, J.R. and Brodie, B.B. (1973). Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J. Pharmacol. Exp. Therap.187:195-202.
42.
Kim, D.H., Yang, K.H., Johnson, K.W. and Holsapple, M.P. (1987). Suppression of in vitro antibody production by dimethylnitrosamine in mixed cultures of mouse primary hepatocytes and mouse splenocytes. Toxicol. Appl. Pharmacol.87:32-42.
43.
Klaassen, C. and Stacey, N.H. (1982). Use of isolated hepatocytes in toxicity assessments . In: Toxicology of the Liver, pp. 147-179. G. Plaa and W.R. Hewitt, eds. Raven Press, New York.
44.
Knadle, S.A., Hanko, V.P., Gordon, G.R., Green, C.E., Peters, J.H. and Tyson, C.A. (1987a). Trichloroethylene metabolism in human and rat hepatocytes and S-9. The Toxicologist7:221.
45.
Knadle, S.A., Green, C.E., Le Valley, S.E., Dabbs, J.E. and Tyson, C.A. (1987b). Benzo(a)pyrene metabolism in human and rat hepatocytes and a comparison of metabolism in suspension and monolayer culture. The Toxicologist7:221.
46.
Kruszyna, R., Kruszyna, H. and Smith, R.P. (1982). Comparison of hydroxylamine, 4-dimethylaminophenol, and nitrite protection against cyanide poisoning in mice. Arch. Toxicol.49:191-202.
47.
Langenbach, R. and Oglesby, L. (1983). The use of intact cellular activation systems in genetic toxicology assay. In: Chemical Mutagens. Principles and Methods for Their Detection, pp. 55-93. F.J. de Serres and A. Hollaender, eds., Plenum Press, NY.
48.
Laskin, D.L., Pilaro, A.M. and Ji, S. (1986). Potential role of activated macrophages in acetaminophen hepatoxicity. II. Mechanism of macrophage accumulation and activation. Toxicol. Appl. Pharmacol.86:216-226.
49.
Lee, C.-C., Ellis, H.V., Kowalski, J.J., Hodgson, J.R., Short, R.D., Bhandari, J.C., Reddig, T.W. and Minor, J.L. (1976). Mammalian Toxicity of Munitions Compounds. Phase II: Effects of Multiple Doses. Part III: 2,6-Dinitrotoluene. Report No. 4., USAMRDC Contract No. DAMD17-74-C-4073, Midwest Research Institute, Kansas City, MO. AD-A062, 015.
50.
Lee, C.-C., Ellis, H.V. III, Kowalski, J.J., Hodgson, J.R., Hwang, S.W., Short, R.D., Bhandari, J.C., Sawyer, J.L., Reddig, T.W. and Minor, J.L. (1978). Mammalian Toxicity of Munition Compounds. Phase II: Effects of Multiple Doses. Part II: 2,4,-Dinitrotoluene. Report No. 3, USAMRDC Contract No. DAMD17-74-C-4073, Midwest Research Institute, Kansas City, MO. AD-A061, 715.
51.
Mcqueen, C.A. and Williams, G.M. (1982). Cytotoxicity of xenobiotics in adult rat hepatocytes in primary culture. Fundam. Appl. Toxicol.2:139-144.
52.
Mcqueen, C.A., Merrill, B.M. and Williams, G.M. (1984). Comparison of several indicators of cytotoxicity in rat hepatocytes in primary culture. The Toxicologist4:134.
53.
Miller, M.G. and Jollow, D.J. (1984). Effect of L-ascorbic acid on acetaminophen-induced hepatotoxicity and covalent binding in hamsters. Evidence that in vitro covalent binding differs from that in vivo. Drug Metab. Dispos.12:271-279.
54.
Mitchell, A.D. and Mirsalis, J.C. (1984). Unscheduled DNA synthesis as an indicator of genotoxic exposure. In: Single-Cell Mutation Monitoring Systems. pp. 165-216. A.A. Ansari and F.J. De Serres , eds. Plenum Publishing, New York.
55.
Mitchell, D.B. and Acosta, D. (1981). Evaluation of the cytotoxicity of tricyclic antidepressants in primary cultures of rat hepatocytes. J. Toxicol. Environ. Health7:83-92.
56.
Mitchell, J.R., Jollow, D.J., Potter, W.Z., Davis, D.C., Gillette, J.R. and Brodie, B.B. (1973). Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J. Pharmacol. Exp. Therap.187:185-194.
57.
Mitoma, C., Tyson, C.A. and Riccio, E.S. (1984). Investigations of the species sensitivity and mechanism of carcinogenicity of halogenated hydrocarbons. Final Report, Contract EPA-68-01-5079, SRI International, Menlo Park, CA.
58.
Mitoma, C., Steeger, T., Jackson, S.E., Wheeler, K.P. and Milman, H.A. (1985). Metabolic disposition study of chlorinated hydrocarbons in rats and mice. Drug Chem. Toxicol.8:183-194.
59.
Moldeus, P. (1978). Paracetamol metabolism and toxicity in isolated hepatocytes from rat and mouse. Biochem. Pharmacol.27:2859-2863.
60.
Moore, M., Thor, H., Moore, G., Nelson, S., Moldeus, P. and Orrenius, S. (1985). The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+. J. Biol. Chem.260:13035-13040.
61.
Orrenius, S. and Ernster, L. (1974). Microsomal cytochrome P-450-linked monooxygenase systems in mammalian tissues. In: Molecular Mechanisms of Oxygen Activation. pp. 215-244. O. Hayaishi, ed. Academic Press, New York.
62.
Perrissoud, D., Auderset, G., Reymond, O. and Maignan, M.F. (1981). The effect of carbon tetrachloride on isolated rat hepatocytes. Early morphological alterations of the plasma membrane. Virchows Arch. [Cell Pathol.]35:83-91.
63.
Peters, J.H., Gordon, G.R., Hanko, V.P., Green, C.E., Knadle, S.A. and Tyson, C.A. (1987). Xenobiotic metabolism by human liver in vitro . Fed. Proc.46:697.
64.
Plaa, G.L. (1976). Quantitative aspects in the assessment of liver injury. Environ. Health Perspect.15:39-46.
65.
Plaa, G.L. (1986). Toxic responses of the liver. In: Casarett and Doull's Toxicology. The Basic Science of Poisons. 3rd Ed, pp. 286-309. C.D. Klaassen, M.O. Amdur, and J. Doull , eds. Macmillan Publishing Co., New York.
66.
Plaa, G.L. and Hewitt, W.R. (1982). Quantitative evaluation of indices of hepatotoxicity . In: Toxicology of the Liver ( G.L. Plaa and W.R. Hewitt, eds.), pp. 103-120. Raven, New York.
67.
Poulsen, J.E., Petersen, P. and Vilstrup, H. (1981). Quantitative liver function and morphology after paracetamol administration to rats. Eur. J. Clin. Invest.11: 161-164.
68.
Rickert, D.E., Butterworth, B.E. and Popp, J.A. (1984). Dinitrotoluene: acute toxicity, oncogenicity, genotoxicity, and metabolism. CRCCrit. Rev. Toxicol.13:217-234.
69.
Rosen, G.M., SINGLETARY, JR., W.V., Rauckman, E.J. and Killenberg , P.G. (1983). Acetaminophen hepatotoxicity. An alternative mechanism. Biochem. Pharmacol.32:2053-2059.
70.
Sato, A. and Nakajima, T. (1979). A structure-activity relationship of some chlorinated hydrocarbons. Arch. Environ. Health10:169-177.
71.
Schnellmann, R.G. and Mandel, L.J. (1986). Cellular toxicity of bromobenzene and bromobenzene metabolites to rabbit proximal tubules: the role and mechanism of 2-bromohydroquinone . J. Pharmacol. Exp. Therap.237:456-461.
72.
Smith, R.F., Fisher, R., Shubat, P.J., Gandolfi, A.J., Krumdieck, C.L. and Brendel, K. (1987). In vitro cytotoxicity of allyl alcohol and bromobenzene in a novel organ culture system. Toxicol. Appl. Pharmacol.87:509-522.
73.
Sina, J.F., Bean, C.L., BLAND, J.A., Macdonald , J.S., NOBLE, C. ROBERTSON, R.T. and BRADLEY, M.O. ( 1986/87). An in vitro assay for cytotoxicity to proximal tubule suspensions from rabbit kidney. In VitroToxicol.1:13-22.
74.
Spanggord, R.J., Tyson, C.A., Myers, C.L., Green, C.E. and Le Valley, S.E. (1985). Development of a Thoretical Model to Assess the Hepatocarcinogenic Potential of Chemicals Using Structure-Activity Relationships and the Rat Hepatocyte Assay. Final Report, Contract No. DAMD17-85-C-5016 , SRI International, Menlo Park, CA.
75.
Stacey, N.H., Priestly, B.G. and Hall, R.C. (1978). Toxicity of halogenated volatile anesthetics in isolated rat hepatocytes. Anesthesiology48:17-22.
76.
Stacey, N.H. and Fanning, J.C. (1981). Ultrastructural changes in isolated rat hepatocytes after incubation with carbon tetrachloride. Toxicology22:69-77.
77.
Story, D.L., Gee, S.J., Tyson, C.A. and Gould, D.H. (1983). Response of isolated hepatocytes to organic and inorganic cytotoxins. J. Toxicol. Environ. Health11:483-501.
78.
Tyson, C.A., Hawk-Prather, K., Story, D.L. and Gould, D.H. (1983a). Correlations of in vitro and in vivo hepatotoxicity for five haloalkanes. Toxicol. Appl. Pharmacol.70:289-302.
79.
Tyson, C.A., Story, D.L. and Stephens, R.J. (1983b). Ultrastructural changes in isolated rat hepatocytes exposed to different CCl4 concentrations. Biochem. Biophys. Res. Commun.114:511-517.
80.
Tyson, C.A., Le Valley, S.E., Chan, R., Hobbs, P.D. and Dawson, M.I. (1984). Biological evaluation of some ionophore-polymeric chelator combinations for reducing Fe overload. J. Pharmacol. Exp. Therap.228:676-681.
81.
Tyson, C.A., Gee, S.J. and Green, C.E. (1987). Mechanism of cyanide-induced cytotoxicity. The Toxicologist7:64.
82.
Tyson, C.A. and Green, C.E. (1987). Cytotoxicity measures: choices and methods. In: The Isolated Hepatocyte. Use in Toxicology and Xenobiotic Biotransformations . pp. 119-158. E.J. Rauckman and G.M. Padilla , eds. Academic Press, New York .
83.
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84.
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85.
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86.
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87.
Zimmerman, H.J., Kendler, J., Libber, S. and Lukacs, L. (1974). Hepatocyte suspensions as a model for demonstration of drug hepatotoxicity. Biochem. Pharmacol.23:2187-2189.
