Selective activation of chemicals by the kidney: its relevance to toxicity and mutagenicity

  • E. A. Lock
  • T. Green


A number of chemicals have been shown to undergo metabolism in the kidney, to metabolites which can covalently bind to macromolecules and produce toxicity. Both paracetamol (McMurtry et al., 1978; Mudge et al., 1978) and chloroform (Ilett et al., 1973; Kluwe et al., 1978) undergo metabolism in the kidney via cytochrome P-450 enzymes to ‘reactive’ metabolites which are thought to be responsible for the cellular necrosis. However, in both these cases, the cytochrome P-450 enzymes are also present in the liver, where these compounds also produce extensive centrilobular necrosis (Mitchell et al., 1973; Ilett et al., 1973). These compounds are therefore not entirely organ selective, and the extent of toxicity to the liver or kidney can be modified by altering the level of activation and deactivation enzymes in these target organs (Mitchell et al., 1973; Ilett et al., 1973; McMurtry et al., 1978; Kluwe et al., 1978).


Renal Tumour Plasma Urea Centrilobular Necrosis Cysteine Conjugate Renal Tubular Necrosis 
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  1. BERGMEYER, H.V. (1963). Methods of enzymatic analysis, pp. 1446–1451, New York: Academic Press.Google Scholar
  2. BERNDT, W.O. & MEHENDALE, H.M. (1979). Effects of hexachlorobutadiene (HCBD) on renal function and renal organic ion transport in the rat. Toxicology, 14, 55–65.PubMedCrossRefGoogle Scholar
  3. BHATTACHARYA, R.K. & SCHULTZE, M.O. (1967). Enzymes from bovine and turkey kidneys which cleave S-(1,2-dichlorovinyl)-L-cysteine. Comp. Biochem. Physiol., 22, 723–735.PubMedCrossRefGoogle Scholar
  4. BHATTACHARYA, R.K. & SCHULTZE, M.O. (1971a). Properties of DNA isolated from tissues of calves treated with S-(1,2-dichlorovinyl)-L-cysteine. I. Chemical and physical properties. Arch. Biochem. Biophys., 145, 565–574.PubMedCrossRefGoogle Scholar
  5. BHATTACHARYA, R.K. & SCHULTZE, M.O. (1971b). Properties of DNA isolated from tissues of calves treated with S-(1,2-dichlorovinyl)-L-cysteine. II. Primer-template activity for bacterial DNA polymerases. Arch. Biochem. Biophys., 145, 575–582.PubMedCrossRefGoogle Scholar
  6. BHATTACHARYA, R.K. & SCHULTZE, M.O. (1972). Properties of DNA treatedwith S-(1,2-dichlorovinyl)-L-cysteine and alyase. Arch. Biochem. Biophys., 153, 105–115.PubMedCrossRefGoogle Scholar
  7. BONHAUS, D.W. & GANDOLFI, A.J. (1981). Conjugation and bioactivation of chlorotrifluoroethylene. Life Sci, 29, 2399–2405.PubMedCrossRefGoogle Scholar
  8. DAVIS, M., BERNDT, W.O. & MEHENDALE, H.M. (1980). Disposition and nephrotoxicity of hexachloro-1:3-butadiene. Toxicology, 16, 179–191.PubMedCrossRefGoogle Scholar
  9. DILLEY, J.V., CARTER, V.L. & HARRIS, E.S. (1974). Fluoride ion excretion by male rats after inhalation of one of several fluoroethylenes or hexafluoropropene. Toxicol. appl. Pharmac., 27, 582–590.CrossRefGoogle Scholar
  10. DOHN, D.R. & ANDERS, M.W. (1982). The enzymatic reaction of chlorotrifluoroethylene with glutathione. Biochem. Biophys. Res. Commun., 109, 1339–1345.PubMedCrossRefGoogle Scholar
  11. GAGE, J.C. (1970). The subacute inhalation toxicity of 109 industrial chemicals. Br. J. Ind. Med., 27, 1–18.PubMedPubMedCentralGoogle Scholar
  12. GANDOLFI, A.J., NAGLE, R.B., SOLTIS, J.J. & PLESCIA, F.H. (1981). Nephro-toxicity of halogenated vinyl cysteine compounds. Res. Comm. Chem. Path. Pharm., 33, 249–261.Google Scholar
  13. GRADISKI, D., DUPRAT, P., MAGADUR, J.L. & FAYEIN, E. (1975). Etude toxicologique experimentale de l’hexachlorobutadiene. Eur. J. Toxicol., 8, 180–187.Google Scholar
  14. GREEN, T. & ODUM, J. (1984). The conjugation and bioactivation of tetrafluoroethylene. Toxicologist, 4, 73.Google Scholar
  15. GREEN, T., ODUM, J. & HOWARD, E.F. (1984). Mutagenic glutathione conjugates of haloalkenes. Toxicologist, 4, 50.Google Scholar
  16. HARD, G.C. & BUTLER, W.H. (1970). Cellular analysis of renal neoplasia: light microscope study of the development of interstitial lesions induced in the rat kidney by a single carcinogenic dose of dimethylnitrosamine. Cancer Res., 30, 2806–2815.PubMedGoogle Scholar
  17. HARLEMAN, J.M. & SEINEN, W. (1979). Short-term toxicity and reproduction studies in rats with hexachlorobutadiene. Toxicol. appl. Pharmac., 47, 1–14.CrossRefGoogle Scholar
  18. ILETT, K.F., REID, W.D., SIPES, I.G. & KRISHNA, G. (1973). Chloroform toxicity in mice: correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules. Exp. Mol. Pathol., 19, 215–229.PubMedCrossRefGoogle Scholar
  19. ISHMAEL, J., PRATT, I.S. & LOCK, E.A. (1982). Necrosis of the pars recta (S3 segment) of the rat kidney produced by hexachloro-1:3-butadiene. J. Path., 138, 99–113.PubMedCrossRefGoogle Scholar
  20. JAFFE, D., HASSALL, C.D., BRENDEL, K. & GANDOLFI, A.J. (1983). In vivo and in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene. Toxicol. Environ. Health, 11, 857–867.CrossRefGoogle Scholar
  21. KLUWE, W.M., McCORMICK, K.M. & HOOK, J.B. (1978). Selective modifications of the renal and hepatic toxicities of chloroform by induction of drug metabolising enzyme systems in kidney and liver. J. Pharmac. exp. Ther., 207, 566–573.Google Scholar
  22. KOCIBA, R.J., KEYES, D.G., JERSEY, G.C., BALLARD, J.J., DITTENBER, D.A., QUAST, J.F., WADE, C.E., HUMISTON, C.G. & SCHWETZ, B.A. (1977). Results of a two year chronic toxicity study with hexachlorobutadiene in rats. Am. Ind. Hyg. Assoc. J., 38, 589–602.PubMedCrossRefGoogle Scholar
  23. LOCK, E.A. & ISHMAEL, J. (1979). The acute toxic effects of hexachlorobutadiene on the rat kidney. Arch. Toxicol., 43, 47–57.PubMedCrossRefGoogle Scholar
  24. LOCK, E.A. & ISHMAEL, J. (1981). Hepatic and renal nonprotein sulphydryl concentration following toxic doses of hexachloro-1:3-butadiene in the rat: the effect of Aroclor 1254, phenobarbitone or SKF 525A treatment. Toxicol. appl. Pharmac., 57, 79–87.CrossRefGoogle Scholar
  25. LOCK, E.A., ISHMAEL, J. & PRATT, I.S. (1982). Hydropic change in rat liver induced by hexachloro-1:3-butadiene. J. Appl. Toxicol., 2, 315–320.PubMedCrossRefGoogle Scholar
  26. McLEAN, A.E.M. & MAGEE, P.N. (1970). Increased renal carcinogenesis by dimethylnitrosamine in protein deficient rats. Br. J. Exp. Path., 51, 587–590.Google Scholar
  27. McMURTRY, R.J., SNODGRASS, W.R. & MITCHELL, J.R. (1978). Renal necrosis, glutathione depletion, and covalent binding after acetaminophen. Toxicol. appl. Pharmac., 46, 87–100.CrossRefGoogle Scholar
  28. MAGEE, P.N. & BARNES, J.M. (1956). The production of malignant primary hepatic tumours in the rat by feeding dimethylnitrosamine. Brit. J. Cancer Res., 10, 114–122.Google Scholar
  29. MAGEE, P.N. & BARNES, J.M. (1962). Induction of kidney tumours in the rat with dimethylnitrosamine. J. Pathol. Bact., 84, 19–31.CrossRefGoogle Scholar
  30. MARSH, W.H., FINGERHUT, B. & MILLER, H.C. (1965). Automated and manual direct methods for the determination of blood urea. Clin. Chem., 11, 624–627.PubMedGoogle Scholar
  31. MITCHELL, J.R., JOLLOW, D.J. , POTTER, W.Z. , GILLETTE, J.R. & BRODIE, B.B. (1973). Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J. Pharmac. exp. Ther., 187, 185–194.Google Scholar
  32. MUDGE, G.J., GEMBORYS, M.W. & DUGGIN, G.G. (1978). Covalent binding of metabolites of acetaminophen to kidney protein and depletion of renal glutathione. J. Pharmac. exp. Ther., 206, 218–226.Google Scholar
  33. NASH, J.A., KING, L.J., LOCK, E.A. & GREEN, T. (1984). The metabolism and disposition of hexachloro-1:3-butadiene in the rat and its relevance to nephrotoxicity. Toxicol. appl. Pharmac., 73, 124–137.CrossRefGoogle Scholar
  34. POTTER, C.L., GANDOLFI, A.J., NAGLE, R. & CLAYTON, J.W. (1981). Effects of inhaled chlorotrifluoroethylene and hexafluoropropene on the rat kidney. Toxicol. appl. Pharmac., 59, 431–440.CrossRefGoogle Scholar
  35. STEVENS, J. & JAKOBY, W.B. (1983). Cysteine conjugate β-lyase. Mol. Pharmac., 23, 761–765.Google Scholar
  36. STOTT, W.T., QUAST, J.F. & WATANABE, P.G. (1981). Differentiation of the mechanisms of oncogenicity of 1,4-dioxane and 1,3-hexachlorobutadiene in the rat. Toxicol. appl. Pharmac., 60, 287–300.CrossRefGoogle Scholar
  37. SWANN, P.F. & McLEAN, A.E.M. (1971). Cellularinjury and carcinogenesis. The effect of a protein free high carbohydrate diet on the metabolism of dimethyl-nitrosamine in the rat. Biochem. J., 124, 283–288.PubMedPubMedCentralCrossRefGoogle Scholar
  38. TERRACINI, B. & PARKER, V.H. (1965). A pathological study of the toxicity of S-(dichlorovinyl)-L-cysteine in the rat. Fd. Cosmet. Toxicol., 3, 67–74.CrossRefGoogle Scholar
  39. TORRETTI, J. & WEINER, I.M. (1976). The renal excretion of drugs. In Methods in Pharmacology, Martinez-Maldonado, M. (ed.), vol. 4A, pp. 357–379, London: Plenum Press.CrossRefGoogle Scholar
  40. WOLF, C.R., BERRY, P.N., NASH, J.A., GREEN, T. & LOCK, E.A. (1984). Role of microsomal and cytosolic glutathione S-transferases in the conjugation of hexachloro-1:3-butadiene and its possible relevance to toxicity. J. Pharmac. exp. Ther., 228, 202–208.Google Scholar

Copyright information

© Macmillan Publishers Limited 1984

Authors and Affiliations

  • E. A. Lock
    • 1
  • T. Green
  1. 1.Biochemical Toxicology SectionCentral Toxicology Laboratory, Imperial Chemical Industries PLCMacclesfieldUK

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