Hepatic Bioactivation of 4-Vinylcyclohexene to Ovotoxic Epoxides

  • Bill J. Smith
  • Donald R. Mattison
  • I. Glenn Sipes
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)


4-Vinylcyclohexene (VCH) is produced by a dimerization reaction of 1,3-butadiene (Rappaport and Fraser, 1976). The curing process of synthetic rubber production results in butadiene dimerization, discharge of VCH, and subsequent exposure of workers to VCH by inhalation (Rappaport and Fraser, 1977). Chronic exposure of humans to VCH may be of concern since a 2 yr bioassay indicated that VCH was carcinogenic to mice (Collins et al., 1987). Chronic gavage of female B6C3F1 mice caused the induction of rare ovarian tumors. These tumors were not observed in VCH-treated Fischer 344 rats (NTP, 1986). Studies in our laboratory have centered on determining the basis for the species difference in VCH-induced ovarian toxicity. Such studies have provided information which may aid in determining which species best predicts the response of humans exposed to VCH. In addition, clues have been obtained pertaining to the mechanism by which VCH produces ovarian injury.


Reactive Intermediate Epoxide Hydrolase Hepatic Microsome P4S0 Form National Toxicology Program 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Collins, J.J., Montali, R.J., and Manus, A.G. (1987). Toxicological evaluation of 4vinylcyclohexene. II. Induction of ovarian tumors in female B6C3F1 mice by 4vinylcyclohexene. J. Toxicol. Environ. Health 21, 507–524.CrossRefPubMedGoogle Scholar
  2. Dobson, R.L. and Felton, J.S. (1983). Female germ cell loss from radiation and chemical exposures. Am. J. Indust. Med. 4, 175–190.CrossRefGoogle Scholar
  3. Halpert, J.R., Naslund, R.B., and Betner, I. (1983). Suicide inactivation of rat liver cytochrome P-450 by chloramphenicol in vivo and in vitro. Mol. Pharmacol. 23, 445–452.PubMedGoogle Scholar
  4. Jull, J.W. (1973). Ovarian tumorigenesis. Methods Cancer Res. 7, 131–186.Google Scholar
  5. Lowry, O.H. Rosebrough, N.J., Farr, A.L., Randall, R.J. (1951). Protein measurement with the folin phenol reagent. J. Biol. Chem. 193, 265–275.PubMedGoogle Scholar
  6. National Toxicology Program (1986). Toxicology and carcinogenesis studies of 4vinylcyclohexene in F344/N rats and B6C3F1 mice. NTP technical report no 303. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Public Information, National Toxicology Program, P.O. box 12333, Research Triangle Park, N.C.Google Scholar
  7. Ota, K. and Hammock, B.D. (1980). Cytosolic and microsomal epoxide hydrolases: Differential properties in mammalian liver. Science 207, 1479–1480.CrossRefPubMedGoogle Scholar
  8. Rappaport, S.M. and Fraser, D.A. (1976). Gas chromatographic-mass spectrometric identification of volatiles released from rubber stock during simulated vulcanization. Anal. Chem. 48, 476–481.CrossRefGoogle Scholar
  9. Rappaport, S.M. and Fraser, D.A. (1977). Air sampling and analysis in a rubber vulcanization area. Am. Ind. Hyg. Assoc. J. 38, 205–209.CrossRefPubMedGoogle Scholar
  10. Shiromizu, K. and Mattison, D.R. (1984). The effect of intraovarian injection of benzo(a)pyrene on primordial oocyte number and ovarian aryl hydrocarbon [benzo(a)pyrene] hydroxylase activity. Toxicol. Appl. Pharmacol. 76, 18–25.CrossRefPubMedGoogle Scholar
  11. Simmon, V.F. and Baden J.M. (1980). Mutagenic activity of vinyl compounds and derived epoxides. Mutat. Res. 78, 227–231.CrossRefPubMedGoogle Scholar
  12. Sipes, I.G. and Gandolfi, A.J. (1986). Biotransformation of toxicants. In Toxicology. The Basic Science of Poisons ( Klaassen, C., Amdur, M., and Doull, J. eds.), pp. 64–98, New York, NY.Google Scholar
  13. Smith, B.J., Mattison, D.R., and Sipes, I.G. (1990a). The role of epoxidation in 4-vinylcyclohexene-induced ovarian toxicity. Toxicol. Appl. Pharmacol., manuscript submitted.Google Scholar
  14. Smith, B.J., Carter, D.E., and Sipes, I.G. (1990b). The disposition and in vitro metabolism of 4-vinylcyclohexene in the female mouse and rat. Toxicol. Appl. Pharmacol., manuscript submitted.Google Scholar
  15. Smith, B.J., Sipes, I.G., Stevens, J.C., and Halpert, J.R. (1990c). The biochemical basis for the species difference in hepatic microsomal 4-vinylcyclohexene epoxidation between female mice and rats. Carcinogenesis, manuscript submitted.Google Scholar
  16. Watabe, T., Hiratsuka, A., Ozawa, N., and Isobe, M. (1981). A comparative study on the metabolism of d-limonene and 4-vinylcylohex-1-ene by hepatic microsomes. Xenobiotica 11, 333–344.CrossRefPubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Bill J. Smith
    • 1
  • Donald R. Mattison
    • 2
  • I. Glenn Sipes
    • 1
  1. 1.Department of Pharmacology and ToxicologyCollege of Pharmacy University of ArizonaTucsonUSA
  2. 2.National Center for Toxicological ResearchJeffersonUSA

Personalised recommendations