Comparative liver metabolism and toxicity of carbon disulfide influenced by various inducers of P450 isoenzymes in rats


  • Departments of Biomedical Sciences, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL 36088
  • Department of Physiology, University of Toronto, Toronto, ON M4Y1R6
  • Departments of Pathobiology, College of Veterinary Medicine, Nursing and Allied Health, Tuskegee University, Tuskegee, AL 36088


Carbon disulfide, cytochrome P450 (CYP), CYP isoenzymes, CYP inducers, hepatotoxicity


The objective of this study was to examine differential metabolism of CS2 by various hepatic cytochrome P450 (CYP) isoenzymes including CYP1A1, CYP2B1, CYP2E1 and CYP3A2 induced by their selective inducers and to determine if there is a correlation between its metabolic activation and hepatotoxicity. Because 3-methylcholanthrene (3-MC), phenobarbital (PB), isoniazid (INH), and pregnenolone-16α-carbonitrile (PCN) are typical selective inducers of CYP1A1, CYP2B1, CYP2E1, and CYP3A2, respectively, they were chosen in this study to pretreat male Sprague-Dawley rats for induction of the CYP isoforms. Twenty-four h following the final dose of 3 daily doses of the inducers, rats were treated ip with a single dose of 380 mg/kg of CS2. Half of the rats in each group were sacrificed at 3 h after CS2 treatment to identify inhibited isoenzymes since CS2 is metabolized by them in a suicide substrate manner. The remaining animals in the group were sacrificed at 24 h following CS2 treatment to determine hepatic damage using serum ALT activity and liver histopathology as the indices of toxicity. At 3 h after treatment, activities of all CYPs (1A1, 2B1, 2E1 and 3A2) were inhibited by CS2 significantly and differentially. However, the inhibition of CYP1A1 and CYP3A2 was reversed at 24 h post-treatment with no serious liver damage. On the other hand, the inhibition of CYP2B1 and CYP2E1 was irreversible and accompanied by severe liver damage especially in phenobarbital-pretreated rats. The results of this study suggest that induced CYP2B1 and to a lesser extent CYP2E1 are responsible for the bioactivation of CS2 and the observed liver damage.


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Arlotto, MP, Sonderfan, AJ, Klaassen, CD and Parkinson, A (1987). Studies on the Pregnenolone-16α-carbonitrileinducible form of rat liver microsomal cytochrome P450 and UDP-glucuronyl transferase. Biochem. Pharmacol., 36: 3859-3866.

Beauchamp, RO, Bus, JS, Popp, JA, Boreiko, CJ and Goldberg, L (1983). A critical review of the literature on carbon disulfide toxicity. CRC Crit. Rev. Toxicol., 11: 169-278.

Bond, E and De Matteis, F (1969). Biochemical changes in rat liver after administration of carbon disulfide, with particular reference to microsomal changes. Biochem. Pharmacol., 18: 2531-2549.

Bond, E, Butler, W, De Matteis, F and Barnes J (1969). Effects of carbon disulfide on the liver of rats. British J. Indust. Med., 26: 335-337.

Bondy, SC and Naderi, S (1994). Contribution of hepatic cytochrome P450 systems to the generation of reactive oxygen species. Biochem. Pharmacol., 48: 155-159.

Burke, MD, Thompson, S, Elcombe, CR, Halpert, J, Haaparanta, T and Mayer, RT (1985). Ethoxy-, pentoxy-, and benzyloxyphenoxazones and homologues: A series of substrates to distinguish between different induced cytochromes P-450. Biochem. Pharmacol. 34: 3337-3345.

De Matteis, F and Seawright, A (1973). Oxidative metabolism of carbon disulfide by the rat: Effect of treatments which modify the liver toxicity of carbon disulfide. ChemicoBiological Interactions, 7: 375-388.

Dalvi, RR, Poore, RE and Neal, RA (1974). Studies of the metabolism of carbon disulfide by rat liver microsomes. Life Sci., 14:1785-1796.

Dalvi, RR, Hunter, A and Neal, RA (1975). Toxicological implications of the mixed-function oxidase catalyzed metabolism of carbon disulfide. Chemico-Biological Interactions, 10: 349-361.

Dalvi, RR and Neal, RA (1978). Metabolism in vivo of carbon disulfide to carbonyl sulfide and carbon dioxide in the rat. Biochem. Pharmacol., 27: 1608-1609.

Dalvi, PS, Dalvi, RR, Wilder-Kofie, T, Mares, B, Lane, C and Billups, LH (2003). Toxicologic implications of the metabolism of thiram, diemethyldithiocarbamate and carbon disulfide mediated by hepatic cytochrome P450 isozymes in rats. Pestic. Biochem. Physiol., 74: 85-89.

Godderis, L, Braeckman, L, Vanhoorne, M and Viaene, M (2006) : Neurobehavioral and clinical effects in workers exposed to CS2. International J. Hygiene and Environ. Hlth., 209: 139-150.

Kivisto, H, Elovaara, E, Riihimaki, V and Aitio, A (1995). Effect of cytochrome P450 isozyme induction and glutathione depletion on the metabolism of CS2 to TTCA in rats. Archives of Toxicol., 69: 185-190.

Koop, DR (1992). Oxidative and reductive metabolism by cytochrome P450 2E1. FASEB J., 6: 724-730.

Le, JY and Fu, XM (1996). Human sperm chromosome analysis”study on human sperm chromosome mutagenesis induced by carbon disulfide. Biomed. and Environ. Sci., 9: 37-40.

Manuel, J (1998). Carbon disulfide neurotoxicity defined. Environ. Hlth. Perspect., 106: A428-432.

Masuda, Y and Yasoshima, M (1988). Loss of 3methylcholanthrene-inducible form of cytochrome P-450 in liver microsomes following administration of carbon disulfide in C57BL/6 Cr mice. Biochem. Pharmacol., 37: 2363-2371.

Morvai, V, Szakmary, E and Ungvary, G (2005). The effects of carbon disulfide and ethanol on the circulatory system of rats. J. Toxicol. Environ. Hlth. A., 68: 787-809.

Patel, KGA, Gautam, K and Vaghasia, YV (1999). Carbon disulphide induced impairments in male reproductive system in rats. Indian J. Physiol.: All. Sci., 53: 22–28.

Price, B, Bergman, TS, Rodriguez, M, Henrich, RT and Moran, EJ (1997). A review of carbon disulfide exposure data and association between carbon disulfide exposure and ischemic heart disease mortality.

Regulatory Toxicol. Pharmacol., 26: 119-128.

Rabkin, JM, Corless, CL, Orloff, SL, Benner, KG, Flora, KD, Rosen, HR and Olyaei, AJ (1998). Liver transplantation for disulfiram-induced hepatic failure. American J. Gastroenterol., 93: 830-831.

Rahman, MA, Grunberg, NE and Mueller, GP (1997). Disulfiram causes sustained behavioral and biochemical effects in rats. Pharmacol. Biochem. Behavior, 56: 409-415.

Smith, PK, Krohn, RI, Hermanson, GT, Mallia, AK, Gartner, FH, Provenzano, MD, Fujimoto, EK, Goeke, NM, Olson, BJ and Klenk, DC (1985). Measurement of protein using bicinchoninic acid. Analytical Biochem., 150: 76-85.

Snyderwine, EG, Kroll, R and Rubin, RJ (1988). The possible role of the ethanol-inducible isozyme of cytochrome P450 in the metabolism and distribution of carbon disulfide. Toxicol. Appl. Pharmacol., 93:11-21.

Tepe, SJ and Zenick, H (1984). The effects of carbon disulfide on the reporoductive system of the male rat. Toxicol., 32: 47-56.

Tsai, ML, Chang, JH, Huang, BM and Liu, MY (2000). In vivo exposure to carbon disulfide increases the contraction frequency of pregnant rat uteri through an indirect pathway. Life Sci., 66: 201-208.

Wronska-Nofer, T, Klimczak, J, Wisniewska-Knypl, J, Jajte, J and Opalska, B (1986). Combined effect of ethanol and carbon disulphide on cytochrome P-450 monooxygenase, lipid peroxidation and ultrastructure of the liver in chronically exposed rats. J. Appl. Toxicol., 6: 297-302.

Wilkie, IW, Seawright, AA and Hrdlicka, J (1985). The hepatotoxicity of carbon disulphide in sheep. J. Appl.

Toxicol., 5: 360-367.



How to Cite

Dalvi, R. R., Dalvi, P. S., & Billups, L. H. (2018). Comparative liver metabolism and toxicity of carbon disulfide influenced by various inducers of P450 isoenzymes in rats. Toxicology International, 16(2), 83–89. Retrieved from



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