Skip to main content
SpringerLink
Log in

Nephrotoxicity and covalent binding of 1,1-dichloroethylene in buthionine sulphoximine-treated mice

  • Original Investigations
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Autoradiography of mice injected i.p. with14C-labelled 1,1-dichloroethylene (vinylidene chloride, VDC) in C57Bl/6 mice revealed a selective covalent binding of radioactivity in the proximal tubules, in the midzonal parts of the liver lobules and in the mucosa of the upper and lower respiratory tract. Since VDC is a renal carcinogen in male mice the effects of compounds modulating biotransformation and glutathione (GSH) levels on the renal covalent binding were examined following a single i.p. dose of14C-VDC. Most pretreatments did not influence the level of binding but treatment with buthionine sulphoximine (BSO), an irreversible inhibitor of gamma-glutamylcysteine synthetase and glutathione (GSH)-depleting agent, increased the renal covalent binding of VDC three-fold. Histopathological examination of kidneys in BSO-pretreated male mice given single i.p. injections of subtoxic doses of VDC (25 and 50 mg/kg) showed necrosis in the proximal tubules (S1 and S2 segments) 24 h following administration. In mice given VDC only, no significant lesions in the kidneys were observed. The severe renal toxicity of VDC in BSO-pretreated mice is suggested to be related to metabolic activation of VDC in the proximal tubules, resulting in further GSH depletion and covalent binding.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Anders MW, Lash L, Dekant W, Elfarra AA, Dohn DR (1988) Biosynthesis and biotransformation of glutathione S-conjugates to toxic metabolites. CRC Crit Rev Toxicol 18: 311–341

    Google Scholar 

  • Bergman K (1979) Whole-body autoradiography and allied tracer techniques in distribution and elimination studies on some organic solvents. Scand J Work Environ Health 5 [Suppl 1]: 1–123

    Google Scholar 

  • Birkel TJ, Roach JAG, Sphon JA (1977) Determination of vinylidene chloride in saran films by electron capture gas solid chromatography and confirmation by mass spectrometry. J Assoc Off Anal Chem 60: 1210–1213

    PubMed  Google Scholar 

  • Brandt I, Brittebo EB (1989) The use of autoradiography as a tool to study xenobiotic metabolism. In: Hutson DH, Caldwell J, Paulson GD (eds) Intermediary xenobiotic metabolism in animals: methodology, mechanisms and significance. Taylor & Francis, London, pp. 295–314

    Google Scholar 

  • Brittebo EB (1989) Uptake and irreversible binding of xenobiotics in the nasal mucosa. In: Feron VJ, Bosland MC (eds) Nasal carcinogenesis in rodents: relevance to human health risk. Pudoc, Wageningen, pp 119–124

    Google Scholar 

  • Brittebo EB, Kowalski B, Ghantous H, Brandt I (1989) Epithelial binding of 1,2-dichloroethane in mice. Toxicology 56: 35–45

    PubMed  Google Scholar 

  • Brittebo EB, Holm C, Brandt I (1990) Metabolic activation and toxicity of bromobenzene in the nasal region of mice. Arch Toxicol 64: 54–60

    PubMed  Google Scholar 

  • Costa AK, Ivanetich KM (1982) Vinylidene chloride: its metabolism by hepatic microsomal cytochrome P450 in vitro. Biochem Pharmacol 31: 2083–2092

    PubMed  Google Scholar 

  • Darnerud PO, Brandt I, Feil VJ, Bakke JE (1988) S-(1,2-Dichloro[14C]vinyl)-L-cysteine (DCVC) in the mouse kidney: correlation between tissue binding and toxicity. Toxicol Appl Pharmacol 95: 423–434

    PubMed  Google Scholar 

  • Darnerud PO, Brandt I, Feil VJ, Bakke JE (1989) Dichlorovinylcysteine (DCVC) in the mouse kidney: tissue-binding and toxicity after glutathione depletion and probenecid treatment. Arch Toxicol 63: 345–350

    PubMed  Google Scholar 

  • Drew R, Miners JO (1984) The effects of buthionine sulphoximine (BSO) on glutathione depletion and xenobiotic biotransformation. Biochem Pharmacol 33: 2989–2994

    PubMed  Google Scholar 

  • Elfarra AA, Jakobsson T, Anders MW (1986) Mechanism of S-(1,2-dichlorovinyl)glutathione-induced nephrotoxicity. Biochem Pharmacol 35: 283–288

    PubMed  Google Scholar 

  • Eriksson C, Brittebo EB (1991) Epithelial binding of 1,1,2,2-tetrachloroethane in the respiratory and upper alimentary tract. Arch Toxicol 65: 10–14

    PubMed  Google Scholar 

  • Forkert PG, Moussa M (1991) 1,1-Dichloroethylene elicits dose dependent alterations in covalent binding and glutathione in murine liver. Drug Metab Dispos 19: 580–586

    PubMed  Google Scholar 

  • Forkert PG, Stringer V, Racz WJ (1986) Effects of administration of metabolic inducers and inhibitors on pulmonary toxicity and covalent binding by 1,1-dichloroethylene in CD-1 mice. Exp Mol Pathol 45: 44–58

    PubMed  Google Scholar 

  • Forkert PG, Hofley M, Racz WJ (1987) Metabolic activation of 1,1-dichloroethylene by mouse and lung liver microsomes. Can J Phys Pharmacol 65: 1496–1499

    Google Scholar 

  • Forkert PG, Geddes BA, Birch DW, Massey TE (1990) Morphologic changes and covalent binding in 1,1-dichloroethylene in Clara and alveolar type 2 cells isolated from lungs of mice following in vivo administration. Drug Metab Dispos 18: 534–539

    PubMed  Google Scholar 

  • Foster JR, Elcombe CR, Boobis AL, Davies DS, Sesardic D, McQuade J, Robson RT, Hayward C, Lock EA (1986) Immunocytochemical localization of cytochrome P-450 in hepatic and extra-hepatic tissues of the rat with a monoclonal antibody against cytochrome P-450c. Biochem Pharmacol 35: 4543–4554

    PubMed  Google Scholar 

  • Gilbert J, Shepherd MJ, Startin JR, McWeeny DJ (1980) Gas Chromatographic determination of vinylidene chloride monomer in packaging films and in foods. J Chromatogr 197: 71–78

    PubMed  Google Scholar 

  • Hu JJ, Rhoten WB, Yang CS (1990) Mouse renal cytochrome P4502E1: Immunocytochemical localization, sexrelated difference and regulation by testosterone. Biochem Pharmacol 40: 2597–2602

    PubMed  Google Scholar 

  • Jackson NM, Conolly RB (1985) Acute nephrotoxicity of 1,1-dichloroethylene in the rat after inhalation exposure. Toxicol Lett 29: 191–199

    PubMed  Google Scholar 

  • Jenkins LJ, Andersen ME (1978) 1,1-Dichloroethylene nephrotoxicity in the rat. Toxicol Appl Pharmacol 46: 131–141

    PubMed  Google Scholar 

  • Jones TW, Qin C, Schaeffer H, Stevens JL (1989) Immunohistochemical localization of glutamine transaminase K, a rat cysteine conjugate β-lyase, and the relationship to the segment specificity of cysteine conjugate nephrotoxicity. Mol Pharmacol 34: 621–627

    Google Scholar 

  • Kowalski B, Brittebo EB, Brandt I (1985) Epithelial binding of 1,2-dibromethane (EDB) in the respiratory and upper alimentary tracts. Cancer Res 45: 2616–2625

    PubMed  Google Scholar 

  • Krijgsheld KR, Lowe MC, Mimnaugh EG, Trush MA, Ginsburg E, Gram T (1984) Selective damage to nonciliated bronchiolar cells in relation to impairment of pulmonary monooxygenase activies by 1,1-dichloroethylene in mice. Toxicol Appl Pharmacol 74: 201–213

    PubMed  Google Scholar 

  • Låg M, Omichinski JG, Söderlund EJ, Brunborg G, Holme JA, Dahl JE, Nelson SD, Dybing E (1989) Role of P450 activity and glutathione levels in 1,2-dibromo-3-chloropropane tissue distribution, renal necrosis and in vivo damage. Toxicology 56: 273–288

    PubMed  Google Scholar 

  • Liebler DC, Meredith MJ, Guengerich FP (1985) Formation of glutathione conjugates by reactive metabolites of vinylidene chloride in microsomes and isolated hepatocytes. Cancer Res 45: 186–193

    PubMed  Google Scholar 

  • Lock EA (1988) Studies on the mechanism of nephrotoxicity and nephrocarcinogenicity of halogenated alkenes. CRC Crit Rev Toxicol 19: 23–42

    Google Scholar 

  • Lowry OH, Rosebrough, NJ, Farrand, AL, Randall, RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193: 265–275

    PubMed  Google Scholar 

  • MacFarlane M, Foster JR, Gibson, GG, King LJ, Lock EA (1989) Cysteine conjugate β-lyase of the rat kidney cytosol: characterization, immunohistochemical localization, and correlation with hexabutadiene nephrotoxicity. Toxicol Appl Pharmacol 98: 185–197

    PubMed  Google Scholar 

  • Maltoni C (1977) Recent findings on the carcinogenicity of chlorinated olefins. Environ Health Perspect 21: 1–6

    PubMed  Google Scholar 

  • Mizutani T, Nomura IH, Nakanishi K (1990) Nephrotoxicity of thiabendazole in mice depleted of glutathione by treatment withDL-buthionine sulphoximine. Food Chem Toxicol 28: 169–177

    PubMed  Google Scholar 

  • Okine LD, Gram TE (1986) In vitro studies on the metabolism and covalent binding of14C-1,1-dichloroethylene by mouse liver, kidney and lung. Biochem Pharmacol 35: 289–295

    PubMed  Google Scholar 

  • Okine LD, Goochee JM, Gram TE (1985) Studies on the distribution and covalent binding of 1,1-dichloroethylene in the mouse. Effect of various pretreatments on covalent binding in vivo. Biochem Pharmacol 34: 4051–4057

    PubMed  Google Scholar 

  • Reed DJ (1990) Glutathione: Toxicological implications. Annu Rev Toxicol 30: 603–631

    Google Scholar 

  • Reitz RH, Watanabe PG, McKenna MJ, Quast JF, Gehring PJ (1980) Effects of vinylidene chloride on DNA synthesis and DNA repair in the rat and mouse: a comparative study with dimethylnitrosamine. Toxicol Appl Pharmacol 52: 357–370

    PubMed  Google Scholar 

  • Sun JD, Dent JG (1980) A new method for measuring protein binding of chemicals to cellular macromolecules. Chem Biol Interact 32: 41–61

    PubMed  Google Scholar 

  • Tjälve H, Löfberg B (1983) Extrahepatic sites of metabolism of carbon tetrachloride Chem Biol Interact 46: 299–316

    PubMed  Google Scholar 

  • Ullberg S (1977) The technique of whole body autoradiography.

  • Cryosectioning of large specimen. Science Tools. LKB Instrument Journal, special issue on whole body autoradiography, pp. 1–29

  • White RD, Norton R, Bus JS (1984) The effect of buthionine sulfoximine, an inhibitor of glutathione synthesis, on hepatic drug metabolism in the male mouse. Toxicol Lett 23: 25–32

    PubMed  Google Scholar 

  • Yost GS, Kuntz DJ, McGill LD (1990) Organ-selective switching of 3-methylindole toxicity by glutathione depletion. Toxicol Appl Pharmacol 103: 40–51

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Lund, Sölvegatan 10, S-22362, Lund, Sweden

    Eva B. Brittebo

  2. Department of Toxicology, University of Uppsala, Box 594, S-75124, Uppsala, Sweden

    Per Ola Darnerud

  3. Department of Pharmacology and Toxicology, SLU, Box 573, S-75123, Uppsala, Sweden

    Catarina Eriksson & Ingvar Brandt

Authors
  1. Eva B. Brittebo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Per Ola Darnerud
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catarina Eriksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ingvar Brandt
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brittebo, E.B., Darnerud, P.O., Eriksson, C. et al. Nephrotoxicity and covalent binding of 1,1-dichloroethylene in buthionine sulphoximine-treated mice. Arch Toxicol 67, 605–612 (1993). https://doi.org/10.1007/BF01974067

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01974067

Keywords

Search

Navigation