Time Course of Hepatic Injury and Recovery Following Coadministration of Carbon Tetrachloride and Trichloroethylene in Fischer-344 Rats

Abstract

Simultaneous administration of trichloroethylene (TCE), at an oral dose of 0.5 ml/kg, resulted in a marked potentiation of liver injury caused by an oral dose of carbon tetrachloride (CCl₄, 0.05 ml/kg). Hepatic glutathione levels were depressed at 24 hr only in the rats given TCE and CCl₄. Using serum enzyme (ALT and SDH) as indicators of hepatotoxicity, potentiation of CCl₄-injury was most apparent at 24 hr. Upon histological examination of H&E stained liver sections, the differences between livers obtained from TCE and CCl₄-treated rats versus CCl₄-treatcd rats were most apparent at later time points (48 and 72 hr). At 48 hr after CCl₄, livers showed a distinctive and uniform pattern of injury with regeneration features predominating over necrosis. At this time, livers from TCE and CCl₄-treated rats were characterized by extensive zone 3 coagulative necrosis. Inflammatory infiltrations were less prominent. At 72 hr, morphological features of livers from TCE and CCl₄ rats were similar to those from rats given CCl₄ alone at 48 hr. From the results obtained, it appears that the regenerative activity of the liver may be delayed in rats simultaneously administered TCE and CCl₄ as compared to rats administered only CCl₄.

Keywords

Interactive hepatotoxicity glutathione synergism alanine aminotransferase sorbitol dehydrogenase halogenated hydrocarbons regeneration

References

1. Bergmeyer HU , Scheibe P , and Wahlefeld AW (1978). Optimization of methods for aspartate aminotransferase and alanine aminotransferase. Clin. Chem 24: 58–73.

2. Blair PC , Thompson MB , Wilson RE , Esber HH , and Maronpot RR (1991). Correlation of changes in serum analytes and hepatic histopathology in rats exposed to carbon tetrachloride. Toxicol. Lett 55:149–159.

3. Borzelleca JF , O'Hara TM , Gennings C , Granger RH , Sheppard MA , and Condie LW Jr (1990). Interactions of water contaminants I. Plasma enzyme activity and response surface methodology following gavage administration of CCl4 and CCl3 or TCE singly and in combination in the rat. Fundam. Appl. Toxicol 14: 477–490.

4. Burmaster DE (1982). The new pollution-ground-water contamination. Environment 24: 7–13, 33–36.

5. Charbonneau M , Oleskevich S , Brodeur J , and Plaa GL (1986). Acetone potentiation of rat liver injury induced by trichloroethylene-carbon tetrachloride mixtures. Fundam. Appl. Toxicol 6: 654–661.

6. Crowley C , Gillham B , and Thorn MB (1975). A direct enzymic method for the determination of reduced glutathione in blood and other tissues. Biochem. Med 13: 287–292.

7. Davies MH , Birt DF , and Schnell RC (1984). Direct enzymatic assay for reduced and oxidized glutathione. J. Pharmacol. Meth 12: 191–194.

8. Harrisch G , and Meyer W (1985). Studies on tissue distribution of glutathione and on activities of glutathione-related enzymes after carbon tetrachloride-induced liver injury. Res. Comm. Chem. Pathol. Pharmacol 47(3): 399–414.

9. Kefalas V and Stacey NH (1989). Potentiation of carbon tetrachloride-induced lipid peroxidation by trichloroethylene in isolated rat hepatocytes: No role in enhanced toxicity. Toxicol. Appl. Pharmacol 101: 158–169.

10.

10. Mehendale HM (1989). Amplification of hepatotoxicity and lethality of CCl4 and CHCl3 by chlordecone. Rev. Biochem. Toxicol 10: 91–138.

11.

11. Meister A (1985). Methods for the selective modification of glutathione metabolism and study of glutathione transport. Meth. Enzymol 113: 571–585.

12.

12. National Research Council (1980). Principles of Toxicological Interactions Associated with Multiple Chemical Exposures National Academy Press, Washington, DC.

13.

13. National Research Council (1989). Drinking Water and Health, Vol. 9: Selected Issues in Risk Assessment National Academy Press, Washington DC.

14.

14. Pessayre D , Cobert B , Descatoire V , DeGott C , Babany G , Funck-Brentano C , Delaforge M , and Larrey D (1982). Hepatotoxicity of trichloroethylene-carbon tetrachloride mixtures in rats. Gastroenterology 83: 761–772.

15.

15. Plaa GL and Hewitt WR (1989). Detection and evaluation of chemically induced liver injury. In: Principles and Methods of Toxicology, 2nd ed., AW Hayes (ed). Raven Press, New York, pp. 599–628.

16.

16. Plaa GL and Vezina M (1990). Factors to consider in the design and evaluation of chemical interaction studies in laboratory animals. In: Toxic Interactions, RS Goldstein , WR Hewitt , and JB Hook (eds). Academic Press, San Diego, pp. 3–30.

17.

17. Recknagel RO , Glende EA , Dolak JA , and Waller RL (1989). Mechanisms of carbon tetrachloride toxicity. Pharmacol. Ther 43: 139–154.

18.

18. Reitman S and Frankel S (1957). A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am. J. Clin. Pathol 28: 56–63.

19.

19. Schnell RC , Bozigian HP , Davies MH , Merrick BA , and Johnson KL (1983). Circadian rhythm in acetaminophen toxicity: Role of nonprotein sulfhydryls. Toxicol. Appl. Pharmacol 71: 353–361.

20.

20. Sipes IG , McMillan DA , Steup DR , and Eskelson C (1991). Synergistic hepatotoxicity in Fischer 344 rats: Effects of trichloroethylene on carbon tetrachloride metabolism and lipid peroxidation. Proceedings of the Fourth International Conference on the Combined Effects of Environmental Factors Archives of Complex Environmental Studies, Baltimore, MD.

21.

21. Sokal RR and Rohlf FJ (1981). Biometry: The Principles and Practice of Statistics in Biological Research, 2nd ed. W. H. Freeman and Co., San Francisco.

22.

22. Steup DR , Weirsma D , McMillan DA , and Sipes IG (1991). Pretreatment with drinking water solutions containing trichloroethylene or chloroform enhances the hepatotoxicity of carbon tetrachloride in Fischer 344 rats. Fundam. Appl. Toxicol 16: 798–809.

23.

23. Wiesner IS , Rawnsley HM , Brooks FP , and Senior JR (1965). Sorbitol dehydrogenase in the diagnosis of liver disease. Am. J. Dig. Dis 10: 147–151.