Skip to main content
NCBI home page
British Journal of Industrial Medicine logoLink to British Journal of Industrial Medicine
. 1991 Sep;48(9):636–642. doi: 10.1136/oem.48.9.636

Ethanol and food deprivation induced enhancement of hepatotoxicity in rats given carbon tetrachloride at low concentration.

H Ikatsu 1, T Okino 1, T Nakajima 1
PMCID: PMC1035437  PMID: 1911407

Abstract

Effects of chronic ethanol consumption and one day food deprivation on the hepatotoxicity of low dose carbon tetrachloride (CCl4; 0 to 100 ppm inhalation for eight hours) in rats were investigated by using biochemical and histopathological methods. Liver malondialdehyde (MDA) contents were significantly increased by exposure to 5 ppm to 50 ppm CCl4 in ethanol treated rats or by exposure to 25 ppm to 50 ppm CCl4 in food deprived rats but not in rats without ethanol or food deprivation. The MDA concentrations reached a maximum at 10 ppm and 50 ppm CCl4 in ethanol treated and food deprived rats, respectively, and decreased to the non-exposed concentration at 100 ppm CCl4. At greater than or equal to 50 ppm CCl4 plasma MDA contents increased significantly only in ethanol treated rats. None of the exposure concentrations influenced plasma glutamic-oxaloacetic transamidase (GOT) and glutamic-pyruvic transaminase (GPT) activities in rats that were only exposed to CCl4 whereas exposure to 10 ppm or higher concentrations combined with ethanol increased both activities. To a lesser extent food deprivation combined with exposure to greater than or equal to 25 ppm CCl4 had the same effect. No histopathological changes were found in the liver of rats exposed to less than or equal to 10 ppm CCl4, and only a few ballooned hepatocytes were seen in centrilobular areas when exposure was 25 ppm or higher. The presence of ballooned and hepatocytes became a regular feature of mid-zonal areas in ethanol treated rats and in the centrilobular areas of food deprived rats after exposure to </= 10 and </=25 ppm CC1(4) respectively. Necrotic hepatocytes were seen in centrilobular areas in liver from ethanol treated and food deprived rats when exposure CC1(4) was >/=25 ppm and >/=50 ppm respectively. These results indicate that consumption of ethanol and food deprivation potentiate CCl(4) induced hepatic damage even at low concentrations of CCl(4) by promoting lipid peroxidation. Thus heavy drinking may be a risk factor for CCl(4) induced hepatic damage even though the CCl(4) concentration is as low as the threshold limit value.

Full text

PDF
636

Images in this article

641Image
on p.641

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ADAMS E. M., SPENCER H. C., ROWE V. K., McCOLLISTER D. D., IRISH D. D. Vapor toxicity of carbon tetrachloride determined by experiments on laboratory animals. AMA Arch Ind Hyg Occup Med. 1952 Jul;6(1):50–66. [PubMed] [Google Scholar]
  2. Andersen M. E. A physiologically based toxicokinetic description of the metabolism of inhaled gases and vapors: analysis at steady state. Toxicol Appl Pharmacol. 1981 Sep 30;60(3):509–526. doi: 10.1016/0041-008x(81)90338-0. [DOI] [PubMed] [Google Scholar]
  3. Brattin W. J., Glende E. A., Jr, Recknagel R. O. Pathological mechanisms in carbon tetrachloride hepatotoxicity. J Free Radic Biol Med. 1985;1(1):27–38. doi: 10.1016/0748-5514(85)90026-1. [DOI] [PubMed] [Google Scholar]
  4. DeCarli L. M., Lieber C. S. Fatty liver in the rat after prolonged intake of ethanol with a nutritionally adequate new liquid diet. J Nutr. 1967 Mar;91(3):331–336. doi: 10.1093/jn/91.3_Suppl.331. [DOI] [PubMed] [Google Scholar]
  5. Fowler J. S. Chlorinated hydrocarbon toxicity in the fowl and duck. J Comp Pathol. 1970 Jul;80(3):465–471. doi: 10.1016/0021-9975(70)90079-4. [DOI] [PubMed] [Google Scholar]
  6. Gömez M. I., de Castro C. R., de Ferreyra E. C., Acosta N. D., de Fenos O. M., Castro J. A. Mechanistic studies on carbon tetrachloride hepatoxicity in fasted and fed rats. Toxicol Appl Pharmacol. 1975 Apr;32(1):101–108. doi: 10.1016/0041-008x(75)90199-4. [DOI] [PubMed] [Google Scholar]
  7. Harris R. N., Ratnayake J. H., Garry V. F., Anders M. W. Interactive hepatotoxicity of chloroform and carbon tetrachloride. Toxicol Appl Pharmacol. 1982 Apr;63(2):281–291. doi: 10.1016/0041-008x(82)90051-5. [DOI] [PubMed] [Google Scholar]
  8. Hewitt W. R., Miyajima H., Côté M. G., Plaa G. L. Acute alteration of chloroform-induced hepato- and nephrotoxicity by n-hexane, methyl n-butyl ketone, and 2,5-hexanedione. Toxicol Appl Pharmacol. 1980 Apr;53(2):230–248. doi: 10.1016/0041-008x(80)90423-8. [DOI] [PubMed] [Google Scholar]
  9. Hong J. Y., Pan J. M., Gonzalez F. J., Gelboin H. V., Yang C. S. The induction of a specific form of cytochrome P-450 (P-450j) by fasting. Biochem Biophys Res Commun. 1987 Feb 13;142(3):1077–1083. doi: 10.1016/0006-291x(87)91525-7. [DOI] [PubMed] [Google Scholar]
  10. Ikatsu H., Nakajima T., Okino T., Murayama N. [Health care of workers engaged in waste water treatment. 1) The exposure conditions to organic solvents in workers engaged in waste water treatment]. Sangyo Igaku. 1989 Sep;31(5):355–362. doi: 10.1539/joh1959.31.355. [DOI] [PubMed] [Google Scholar]
  11. Jaeger R. J., Conolly R. B., Murphy S. D. Short-term inhalation toxicity of halogenated hydrocarbons: effects on fasting rats. Arch Environ Health. 1975 Jan;30(1):26–31. doi: 10.1080/00039896.1975.10666628. [DOI] [PubMed] [Google Scholar]
  12. Johansson I., Ekström G., Scholte B., Puzycki D., Jörnvall H., Ingelman-Sundberg M. Ethanol-, fasting-, and acetone-inducible cytochromes P-450 in rat liver: regulation and characteristics of enzymes belonging to the IIB and IIE gene subfamilies. Biochemistry. 1988 Mar 22;27(6):1925–1934. doi: 10.1021/bi00406a019. [DOI] [PubMed] [Google Scholar]
  13. Johansson I., Ingelman-Sundberg M. Carbon tetrachloride-induced lipid peroxidation dependent on an ethanol-inducible form of rabbit liver microsomal cytochrome P-450. FEBS Lett. 1985 Apr 22;183(2):265–269. doi: 10.1016/0014-5793(85)80790-0. [DOI] [PubMed] [Google Scholar]
  14. Kalyanaraman B., Mason R. P., Perez-Reyes E., Chignell C. F., Wolf C. R., Philpot R. M. Characterization of the free radical formed in aerobic microsomal incubations containing carbon tetrachloride and NADPH. Biochem Biophys Res Commun. 1979 Aug 28;89(4):1065–1072. doi: 10.1016/0006-291x(79)92116-8. [DOI] [PubMed] [Google Scholar]
  15. Klaassen C. D., Plaa G. L. Relative effects of various chlorinated hydrocarbons on liver and kidney function in mice. Toxicol Appl Pharmacol. 1966 Jul;9(1):139–151. doi: 10.1016/0041-008x(66)90038-x. [DOI] [PubMed] [Google Scholar]
  16. Kornbrust D. J., Mavis R. D. Microsomal lipid peroxidation. II. Stimulation by carbon tetrachloride. Mol Pharmacol. 1980 May;17(3):408–414. [PubMed] [Google Scholar]
  17. Lieber C. S. Metabolic effects of ethanol and its interaction with other drugs, hepatotoxic agents, vitamins, and carcinogens: a 1988 update. Semin Liver Dis. 1988 Feb;8(1):47–68. doi: 10.1055/s-2008-1040528. [DOI] [PubMed] [Google Scholar]
  18. Macdonald C. M., Dow J., Moore M. R. A possible protective role for sulphydryl compounds in acute alcoholic liver injury. Biochem Pharmacol. 1977 Aug 15;26(16):1529–1531. doi: 10.1016/0006-2952(77)90428-2. [DOI] [PubMed] [Google Scholar]
  19. Mihara M., Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem. 1978 May;86(1):271–278. doi: 10.1016/0003-2697(78)90342-1. [DOI] [PubMed] [Google Scholar]
  20. Mitchell J. R., Jollow D. J., Potter W. Z., Davis D. C., Gillette J. R., Brodie B. B. Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther. 1973 Oct;187(1):185–194. [PubMed] [Google Scholar]
  21. Nakajima T., Elovaara E., Park S. S., Gelboin H. V., Hietanen E., Vainio H. Immunochemical characterization of cytochrome P-450 isozymes responsible for benzene oxidation in the rat liver. Carcinogenesis. 1989 Sep;10(9):1713–1717. doi: 10.1093/carcin/10.9.1713. [DOI] [PubMed] [Google Scholar]
  22. Nakajima T., Elovaara E., Park S. S., Gelboin H. V., Hietanen E., Vainio H. Monoclonal antibody-directed characterization of benzene, ethoxyresorufin and pentoxyresorufin metabolism in rat liver microsomes. Biochem Pharmacol. 1990 Sep 15;40(6):1255–1261. doi: 10.1016/0006-2952(90)90391-w. [DOI] [PubMed] [Google Scholar]
  23. Nakajima T., Wang R. S., Elovaara E., Park S. S., Gelboin H. V., Hietanen E., Vainio H. Monoclonal antibody-directed characterization of cytochrome P450 isozymes responsible for toluene metabolism in rat liver. Biochem Pharmacol. 1991 Feb 1;41(3):395–404. doi: 10.1016/0006-2952(91)90536-e. [DOI] [PubMed] [Google Scholar]
  24. Paustenbach D. J., Clewell H. J., 3rd, Gargas M. L., Andersen M. E. A physiologically based pharmacokinetic model for inhaled carbon tetrachloride. Toxicol Appl Pharmacol. 1988 Nov;96(2):191–211. doi: 10.1016/0041-008x(88)90080-4. [DOI] [PubMed] [Google Scholar]
  25. Ramsey J. C., Andersen M. E. A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans. Toxicol Appl Pharmacol. 1984 Mar 30;73(1):159–175. doi: 10.1016/0041-008x(84)90064-4. [DOI] [PubMed] [Google Scholar]
  26. Sabourin P. J., Bechtold W. E., Griffith W. C., Birnbaum L. S., Lucier G., Henderson R. F. Effect of exposure concentration, exposure rate, and route of administration on metabolism of benzene by F344 rats and B6C3F1 mice. Toxicol Appl Pharmacol. 1989 Jul;99(3):421–444. doi: 10.1016/0041-008x(89)90151-8. [DOI] [PubMed] [Google Scholar]
  27. Sipes I. G., Krishna G., Gillette J. R. Bioactivation of carbon tetrachloride, chloroform and bromotrichloromethane: role of cytochrome P-450. Life Sci. 1977 May 1;20(9):1541–1548. doi: 10.1016/0024-3205(77)90446-5. [DOI] [PubMed] [Google Scholar]
  28. Slater T. F. Free-radical mechanisms in tissue injury. Biochem J. 1984 Aug 15;222(1):1–15. doi: 10.1042/bj2220001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Strubelt O., Obermeier F., Siegers C. P., Vöpel M. Increased carbon tetrachloride hepatotoxicity after low-level ethanol consumption. Toxicology. 1978 Jul;10(3):261–270. doi: 10.1016/0300-483x(78)90076-8. [DOI] [PubMed] [Google Scholar]
  30. Tateishi N., Higashi T., Shinya S., Naruse A., Sakamoto Y. Studies on the regulation of glutathione level in rat liver. J Biochem. 1974 Jan;75(1):93–103. doi: 10.1093/oxfordjournals.jbchem.a130387. [DOI] [PubMed] [Google Scholar]
  31. Teschke R., Vierke W., Gellert J. Effect of ethanol on carbon tetrachloride levels and hepatotoxicity after acute carbon tetrachloride poisoning. Arch Toxicol. 1984 Dec;56(2):78–82. doi: 10.1007/BF00349075. [DOI] [PubMed] [Google Scholar]
  32. Thomas P. E., Reik L. M., Maines S. L., Bandiera S., Ryan D. E., Levin W. Antibodies as probes of cytochrome P450 isozymes. Adv Exp Med Biol. 1986;197:95–106. doi: 10.1007/978-1-4684-5134-4_8. [DOI] [PubMed] [Google Scholar]
  33. Uemitsu N. Inhalation pharmacokinetics of carbon tetrachloride in rats based on arterial blood:inhaled air concentration ratios. Toxicol Appl Pharmacol. 1986 Mar 30;83(1):20–29. doi: 10.1016/0041-008x(86)90319-4. [DOI] [PubMed] [Google Scholar]
  34. Uemitsu N., Minobe Y., Nakayoshi H. Concentration-time-response relationship under conditions of single inhalation of carbon tetrachloride. Toxicol Appl Pharmacol. 1985 Feb;77(2):260–266. doi: 10.1016/0041-008x(85)90325-4. [DOI] [PubMed] [Google Scholar]
  35. de Groot H., Noll T. Halomethane hepatotoxicity: induction of lipid peroxidation and inactivation of cytochrome P-450 in rat liver microsomes under low oxygen partial pressures. Toxicol Appl Pharmacol. 1989 Mar 1;97(3):530–537. doi: 10.1016/0041-008x(89)90258-5. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Industrial Medicine are provided here courtesy of BMJ Publishing Group

RESOURCES