The Nephrotoxicity of Haloalkane and Haloalkene Glutathione Conjugates

  • Edward A. Lock


The kidneys are susceptible to the toxicity of a large number of chemicals, although the precise mechanisms of renal injury are not well understood (Maher, 1976; Kluwe, 1981; Hook et al., 1979; Lock, 1982; Rush et al., 1984). This chapter will discuss the mechanism(s) whereby a small number of halogenated chemicals undergo metabolism to form glutathione conjugates. Glutathione conjugates are frequently less toxic than their parent compounds and are eliminated in the bile or after bio-transformation to mercapturic acids, in the urine. However, glutathione conjugation has been also implicated in the formation of reactive intermediates. In the kidney, at least two different mechanisms have been reported for glutathione dependent generation of reactive intermediates. The first mechanism involves the conjugation of 1,2-dihaloethanes with glutathione. The S-(2-haloethyl)glutathione formed may then rearrange to give a highly reactive ethylene-S-glutathionyl episulphonium ion (Livesey and Anders, 1979; Van Bladeren et al., 1980; Hill et al., 1978) or undergo degradation to S-(2-haloethyl)-L-cysteine prior to rearranging to give the episulphonium ion (Schasteen and Reed, 1983; Elfarra et al., 1985). This reactive episulphonium ion can then react with nucleophilic groups in various macromolecules to produce toxicity. The second mechanism of glutathione dependent metabolic activation involves the formation of stable glutathione conjugates in the liver which are degraded to their cysteine conjugates, concentrated in renal cells and activated by the renal enzyme cysteine conjugate β-lyase (Lock and Green, 1984).


Proximal Tubule Proximal Tubular Cell Organic Anion Transport Glutathione Conjugate Mercapturic Acid 
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. Anderson, P. M. and Schultze, M. O. (1965). Cleavage of S-(l,2-dichlorovinyl)-L-cysteine by an enzyme of bovine origin. Arch. Biochem. Biophys., 111, 593–602Google Scholar
  2. Banerjee, S. and Van Durren, B. L. (1979). Binding of carcinogenic halogenated hydrocarbons to cell macromolecules. J. Nat. Cancer. Inst., 63, 707–11PubMedGoogle Scholar
  3. Berndt, W. O. and Mehendale, H. M. (1979). Effects of hexachlorobutadiene (HCBD) on renal function and renal organic ion transport in the rat. Toxicology, 14, 55–65PubMedCrossRefGoogle Scholar
  4. Bhattacharya, R. K. and Schultze, M. O. (1967). Enzymes in bovine and turkey kidneys which cleave S-(l,2-dichlorovinyl)-L-cysteine. Comp. Biochem. Physiol., 22, 723–35PubMedCrossRefGoogle Scholar
  5. Bhattacharya, R. K. and Schultze, M. O. (1972). Properties of DNA treated with S-(l,2-dichlorovinyl)-L-cysteine and a lyase. Arch. Biochem. Biophys., 153, 105–15PubMedCrossRefGoogle Scholar
  6. Bonhaus, D. W. and Gandolfi, A. J. (1981). Conjugation and bioactivation of chlorotrifluoroethylene. Life Sci., 29, 2399–405PubMedCrossRefGoogle Scholar
  7. Boyd, M. R. and Dutcher, J. S. (1981). Renal toxicity due to reactive metabolites formed in situ in the kidney: investigations with 4-ipomeanol in the mouse. J. Pharmacol. exptl. Ther., 216, 640–6Google Scholar
  8. Branchflower, R. V., Nunn, D. S., Highet, R. J., Smith, J. H., Hook, J. B. and Pohl, L. R. (1984). Nephrotoxicity of chloroform: metabolism to phosgene by the mouse kidney. Toxicol. appl. Pharmacol., 72, 159–68PubMedCrossRefGoogle Scholar
  9. Buckley, L. A., Clayton, J. W., Nagle, R. B. and Gandolfi, A. J. (1982). Chlorotri-fluoroethylene nephrotoxicity in rats: a subacute study. Fund. appl. Toxicol., 2, 181–6CrossRefGoogle Scholar
  10. Cater, D. B. and Peters, R. A. (1961). The occurrence of renal changes resembling nephrosis in rats poisoned with fluorocitrate. Brit. J. exptl. Path., 42, 278–89Google Scholar
  11. Chasseaud, L. F. (1979). The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Adv. Cancer Res., 29, 175–274PubMedCrossRefGoogle Scholar
  12. Clayton, J. W. (1977). Toxicology of the fluoroalkenes: review and research needed. Environ. Hlth Perspec, 21, 255–67CrossRefGoogle Scholar
  13. Davis, M. E. (1984). AT-125 (acividin) does not prevent hexachlorobutadiene (HCBD) nephrotoxicity. Toxicologist, 4, 32Google Scholar
  14. Davis, M. E., Berndt, W. O. and Mehendale, H. M. (1980). Disposition and nephrotoxicity of hexachloro-1,3-butadiene. Toxicology, 16, 179–91PubMedCrossRefGoogle Scholar
  15. Dees, J. H., Masters, B. S. S., Muller-Eberhard, U. and Johnson, E. F. (1982). Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin and phenobarbitone on the occurrence and distribution of four cytochrome P-450 isoenzymes in rabbit kidney. Cancer Res., 42, 1423–32Google Scholar
  16. Dilley, J. V., Carter, V. L. and Harris, E. S. (1974). Fluoride ion excretion by male rats after inhalation of one of several fluoroethylenes or hexafluoropropene. Toxicol. appl Pharmacol., 27, 582–90PubMedCrossRefGoogle Scholar
  17. Dohn, A. R. and Anders, M. W. (1982a). The enzymatic reaction of chlorotrifluoro-ethylene with glutathione. Biochem. Biophys. Res. Commun., 109, 1339–45PubMedCrossRefGoogle Scholar
  18. Dohn, A. R. and Anders, M. W. (1982b). Assay of cysteine conjugate β-lyase activity with S-(2-benzothiazolyl)cysteine as the substrate. Anal. Biochem., 120, 379–86PubMedCrossRefGoogle Scholar
  19. Duffel, M. and Jakoby, W. B. (1982). Cysteine S-conjugate N-acetyl-transferase from rat kidney microsomes. Mol. Pharm., 21, 444–8Google Scholar
  20. Duggin, G. G. and Mudge, G. H. (1976). Analgesic nephropathy: renal distribution of acetaminophen and its conjugates. J. Pharmacol exptl Ther., 199, 1–9Google Scholar
  21. Earl, L. K., McLean, A. E. M. and Lock, E. A. (1984). Use of isolated kidney cells for studying nephrotoxicity: hexachloro-1,3-butadiene as a model compound. Human Toxicol., 3, 332–3Google Scholar
  22. Elfarra, A. A. and Anders, M. W. (1984). Renal processing of glutathione conjugates: role in nephrotoxicity. Biochem. Pharmacol., 33, 3729–32PubMedCrossRefGoogle Scholar
  23. Elfarra, A. A., Baggs, R. B. and Anders, M. W. (1985). Structure-nephrotoxicity relationships of S-(2-chloroethyl)-DL-cysteine and analogs: role for an episul-phonium ion. J. Pharmacol. exptl Ther., 233, 512–16Google Scholar
  24. Fowler, B. A., Hook, G. E. R. and Lucier, G. W. (1977). Tetrachlorodibenzo-p-dioxin induction of renal microsomal enzyme systems. Ultrastructural effects on pars recta (S3) proximal tubule cells of the rat kidney. J. Pharmacol. exptl. Ther., 203, 712–21Google Scholar
  25. Fry, J. R., Wiebkin, P., Kao, J., Jones, C. A., Gwynn, J. and Bridges, J. W. (1978). A comparison of drug-metabolising capability in isolated viable rat hepatocytes and renal tubule fragments. Xenobiotica, 8, 113–20PubMedCrossRefGoogle Scholar
  26. Gandolfi, A. J., Nagle, R. B., Soltis, J. J. and Plescia, F. H. (1981). Nephrotoxicity of halogenated vinyl cysteine compounds. Res. Comm. Path. Pharmacol., 33, 249–61Google Scholar
  27. Ganote, C. E., Reimer, K. A. and Jennings, R. B. (1974). Acute mercury chloride nephrotoxicity, an electron microscopic and metabolic study. Lab. Invest., 31, 633–47PubMedGoogle Scholar
  28. Gerdes, R. G., Jones, T. W., Ormstad, K. and Orrenius, S. (1985). The formation of glutathione conjugates of hexachlorobutadiene by isolated liver cells. In Renal Heterogeneity and Target Cell Toxicity (eds P. H. Bach and E. A. Lock), John Wiley, Chichester, pp. 145–8Google Scholar
  29. Glaumann, B. and Trump, B. F. (1975). Studies on the pathogenesis of ischemic cell injury. III Morphological changes of the proximal pars recta tubules (P3) of the rat kidney made ischemic in vivo. Virchows. Arch. B. Cell. Path., 19, 303–23Google Scholar
  30. Gradiski, D., Duprat, P., Magadur, J-L. and Fayein, E. (1975). Etude toxicologique experimentale de l’hexachlorobutadiene. Eur. J. Toxicol., 8, 180–7Google Scholar
  31. Grafstrom, R., Ormstad, K., Moldeus, P. and Orrenius, S. (1979). Paracetamol metabolism in the isolated perfused rat liver with further metabolism of biliary conjugate by small intestines. Biochem. Pharmacol., 28, 3573–9PubMedCrossRefGoogle Scholar
  32. Green, R. M. and Elce, J. S. (1975). Acetylation of S-substituted cysteines by a rat liver and kidney microsomal N-acetyltransferase. Biochem. J., 147, 283–9PubMedPubMedCentralCrossRefGoogle Scholar
  33. Green, T. and Odum, J. (1985). Structure/activity studies of the nephrotoxic and mutagenic action of cysteine conjugates of chloro and fluoroalkenes. Chem. Biol. Interac., 54, 15–31CrossRefGoogle Scholar
  34. Guengerich, F. P., Crawford, W. M., Domoradzki, J. Y., Macdonald, T. L. and Watanabe, P. G. (1980). In vitro activation of 1,2-dichloroethane by microsomal and cytosolic enzymes. Toxicol. appl. Pharmacol., 55, 303–17PubMedCrossRefGoogle Scholar
  35. Harleman, J. H. and Seinen, W. (1979). Short-term toxicity and reproduction studies in rats with hexachloro-1,3-butadiene. Toxicol. appl. Pharmacol., 47, 1–14Google Scholar
  36. Hassall, C. D., Gandolfi, A. J. and Brendel, K. (1983). Effect of halogenated vinyl cysteine conjugates on renal tubular active transport. Toxicology, 26, 285–94PubMedCrossRefGoogle Scholar
  37. Hassall, C. D., Gandolfi, A. J., Duhamel, R. C. and Brendel, K. (1984). The formation and biotransformation of cysteine conjugates of halogenated ethylenes by rabbit renal tubules. Chem. Biol. Interac., 49, 283–97CrossRefGoogle Scholar
  38. Hill, D. L., Shih, T. W., Johnston, T. P. and Struck, R. F. (1978). Macromolecular binding and metabolism of the carcinogen 1,2-dibromoethane. Cancer Res., 38, 2438–42PubMedGoogle Scholar
  39. Hirata, E. and Takahashi, H. (1981). Degradation of methyl mercury glutathione by the pancreatic enzymes in bile. Toxicol. appl Pharmacol., 58, 483–91PubMedCrossRefGoogle Scholar
  40. Hook, J. B., McCormack, K. M. and Kluwe, W. M. (1979). Biochemical mechanisms of nephrotoxicity. Rev. Biochem. Toxicol, 1, 53–78Google Scholar
  41. Hook, J. B., Ishmael, J. and Lock, E. A. (1983). Nephrotoxicity of hexachloro-1,3-butadiene in the rat: the effect of age, sex and strain. Toxicol. appl. Pharmacol., 67, 121–31Google Scholar
  42. Ilett, K. F., Reid, W. D., Sipes, I. G. and Krishna, G. (1973). Chloroform toxicity in mice: correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules. Exptl. mol. Pathol., 19, 215–29CrossRefGoogle Scholar
  43. Inoue, M., Okajima, K. and Morino, Y. (1981). Renal transtubular transport of mercapturic acid in vivo. Biochim. Biophys. Acta, 641, 122–8PubMedCrossRefGoogle Scholar
  44. Inoue, M., Okajima, K. and Morino, Y. (1982). Metabolic co-ordination of liver and kidney in mercapturic acid biosynthesis in vivo. Hepatology, 2, 311–16PubMedCrossRefGoogle Scholar
  45. Inoue, M., Okajima, K. and Morino, Y. (1984). Hepato-renal cooperation in bio-transformation, membrane transport and elimination of cysteine S-conjugates of xenobiotics. J. Biochem. (Tokyo), 95, 247–54Google Scholar
  46. Inskeep, P. R. and Guengerich, F. P. (1984). Glutathione-mediated binding of dibromoalkanes to DNA: specificity of rat glutathione-S-transferases and di-bromoalkane structure. Carcinogenesis, 5, 805–8PubMedCrossRefGoogle Scholar
  47. Jacobsen, N. O. and Jorgensen, F. (1973). Ultrastructural observations on pars descendens of the proximal tubule in the kidney of the male rat. Z. Zellforsch. Mikrosk. Anat., 136, 479–99CrossRefGoogle Scholar
  48. Jaffe, D. R., Hassall, C. D., Brendel, K. and Gandolfi, A. J. (1983). In vivo and in vitro nephrotoxicity of the cysteine conjugate of hexachlorobutadiene. J. Toxicol. Environ. Hlth., 11, 857–67CrossRefGoogle Scholar
  49. Jaffe, D. R., Gandolfi, A. J. and Nagle, R. B. (1984). Chronic toxicity of S-(trans-1,2-dichlorovinyl)-L-cysteine in mice. J. appl. Toxicol., 4, 315–19PubMedCrossRefGoogle Scholar
  50. Jakoby, W. B. and Habig, W. H. (1980). Glutathione transferases. In: Enzymatic Basis of Detoxication, Vol. II (ed. W. B. Jakoby), Academic Press, New York, pp.63–94Google Scholar
  51. Jakoby, W. B., Stevens, J., Duffel, M. W. and Weisiger, R. A. (1984). The terminal enzymes of mercapturate formation and the thiomethyl shunt. Rev. Biochem. Toxicol., 6, 95–115Google Scholar
  52. Johnson, M. K. (1965). The influence of some aliphatic compounds on rat liver glutathione levels. Biochem. Pharmacol., 14, 1383–5PubMedCrossRefGoogle Scholar
  53. Kluwe, W. M. (1981). The nephrotoxicity of low molecular weight halogenated alkane solvents, pesticides and chemical intermediates. In: Toxicology of the Kidney (ed. J. B. Hook), Raven Press, New York, pp. 179–226Google Scholar
  54. Kluwe, W. M., McNish, R., Smithson, K. and Hook, J. B. (1981). Depletion by 1,2-dibromoethane, 1,2- dibromo-3-chloropropane, tris(2,3-dibromopropyl)-phosphate and hexachloro-1,3-butadiene of reduced non-protein sulphydryl groups in target and nontarget organs. Biochem. Pharmacol., 30, 2265–771PubMedCrossRefGoogle Scholar
  55. Kluwe, W. M., Abdo, K. M. and Huff, J. (1984). Chronic kidney disease and organic chemical exposures: evaluations of casual relationships in humans and experimental animals. Fund. appl. Toxicol., 4, 889–901CrossRefGoogle Scholar
  56. Kociba, R. J., Schweiz, B. A., Keyes, D. G., Jersey, G. C, Ballard, J. J., Dittenber, D. A., Quast, J. F., Wade, C. E. and Humiston, C. G. (1977a). Chronic toxicity and reproduction studies of hexachlorobutadiene in rats. Environ. Hlth. Per-spect., 21, 49–53CrossRefGoogle Scholar
  57. Kociba, R. J., Keyes, D. G., Jersey, G. C, Ballard, J. J., Dittenber, D. A., Quast, J. F., Wade, C. E., Humiston, C. G. and Schwetz, B. A. (1977b). Results of a two year chronic toxicity with hexachlorobutadiene in rats. Am. Ind. Hyg. Assoc. J., 38, 589–602PubMedCrossRefGoogle Scholar
  58. Kozak, E. M. and Tate, S. S. (1982). Glutathione-degrading enzymes of microvillus membranes. J. Biol. Chem., 257, 6322–7PubMedGoogle Scholar
  59. Larsen, G. L., Larson, J. D. and Gustafsson, J-A. (1983). Cysteine conjugate β-lyase in the gastrointestinal bacterium Fusobacterium necrophorum. Xenobiotica, 13, 689–700PubMedCrossRefGoogle Scholar
  60. Lash, L. H. and Jones, D. P. (1983). Transport of glutathione by renal basal-lateral membrane vesicles. Biochem. Biophys. Res. Commun., 112, 55–60PubMedCrossRefGoogle Scholar
  61. Lash, L. H. and Jones, D. P. (1984). Renal glutathione transport. Characteristics of the sodium-dependent system in the basal-lateral membrane. J. Biol. Chem., 259, 14508–14PubMedGoogle Scholar
  62. Lash, L. H. and Jones, D. P. (1985). Uptake of the glutathione conjugate S-(l,2-di-chlorovinyl)glutathione by renal basal-lateral membrane vesicles and isolated kidney cells. Mol. Pharm., 28, 278–82Google Scholar
  63. Litterst, C. L., Mimnaugh, E. G., Reagan, R. L. and Gram, T. E. (1975). Comparison of in vitro drug metabolism by lung, liver and kidney of several common laboratory species. Drug. Metab. Dispos., 3, 259–65PubMedGoogle Scholar
  64. Litterst, C. L., Mimnaugh, E. G. and Gram, T. E. (1977). Comparative alterations in extrahepatic drug metabolism by factors known to affect hepatic activity. Biochem. Pharmacol., 26, 749–55PubMedCrossRefGoogle Scholar
  65. Livesey, J. C. and Anders, M. W. (1979). In vitro metabolism of 1,2-dihaloethanes to ethylene. Drug Metab. Dispos., 7, 199–203PubMedGoogle Scholar
  66. Lock, E. A. (1982). Renal necrosis produced by halogenated chemicals. In: Nephrotoxicity: Assessment and Pathogenesis (eds P. H. Bach, F. W. Bonner, J. W. Bridges and E. A. Lock), John Wiley, Chichester, pp. 396–408Google Scholar
  67. Lock, E. A. and Green, T. (1984). Selective activation of chemicals by the kidney: its relevance to toxicity and mutagenicity. In: Proceedings 9th International Congress of Pharmacology, Vol. 1, (eds W. Paton, J. Mitchell and P. Turner) Macmillan, London, pp. 197–202Google Scholar
  68. Lock, E. A. and Ishmael, J. (1979). The acute toxic effects of hexachloro-1,3-butadiene on the rat kidney. Arch. Toxicol., 43, 47–57PubMedCrossRefGoogle Scholar
  69. Lock, E. A. and Ishmael, J. (1981). Hepatic and renal non-protein 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. Pharmacol., 57, 79–87PubMedCrossRefGoogle Scholar
  70. Lock, E. A. and Ishmael, J. (1985). Effect of the organic acid transport inhibitor probenecid on renal cortical uptake and proximal tubular toxicity of hexachloro-1,3-butadienylcysteine by rat renal cortex. Arch. Toxicol., 59, 12–15CrossRefGoogle Scholar
  71. Lock, E. A., Ishmael, J. and Hook, J. B. (1984). Nephrotoxicity of hexachloro-1,3-butadiene in the mouse: the effect of age, sex, strain, monooxygenase modifiers, and the role of glutathione. Toxicol. appl. Pharmacol., 72, 484–94PubMedCrossRefGoogle Scholar
  72. Lock, E. A., Odum, J. and Ormond, P. (1986). Transport of N-acetyl-S-penta-chloro-1,3-butadienylcysteine by rat renal cortex. Arch. Toxicol., in pressGoogle Scholar
  73. McIntyre, T. and Curthoys, N. P. (1982). Renal catabolism of glutathione. J. Biol. Chem., 257, 11915–21PubMedGoogle Scholar
  74. McKinney, L. L., Picken, J. C, Weakley, F. B., Eldridge, A. C, Campbell, R. E., Cowan, J. C. and Biester, H. E. (1959). Possible toxic factor of trichloroethylene-extracted soybean oil meal. J. Am. chem. Soc., 81, 909–15CrossRefGoogle Scholar
  75. Maher, J. F. (1976). Toxic nephropathy. In: The Kidney (eds B. M. Brenner and F. C. Rector), Saunders, Philadelphia, pp. 1355–95Google Scholar
  76. Massey, V. and Williams, C. H. (1965). On the reaction mechanism of yeast glutathione reductase. J. Biol. Chem., 240, 4470–80PubMedGoogle Scholar
  77. Maunsbach, A. B. (1966). Observations on the segmentation of the proximal tubule in the rat kidney. J. ultrastruct. Res., 16, 239–58PubMedCrossRefGoogle Scholar
  78. Monks, T. J., Lau, S. S. and Gillette, J. R. (1983). Glutathione conjugates of 2-bromohydroquinone, a metabolite of bromobenzene are nephrotoxic. In: Abstracts of 1st Int. Symp. on Foreign Compound Metabolism, West Palm Beach, Florida, USA, 30th October-4th November, p.48Google Scholar
  79. Monks, T. J., Lau, S. S. and Gillette, J. R. (1984). The metabolism and nephrotoxicity of 2-bromohydroquinone glutathione conjugates. In: Abstracts of 6th Int. Symp. on Microsomes and Drug Oxidation, Brighton, Sussex, UK, 5th-10th August, p.23Google Scholar
  80. Mudge, G. H., Gemborys, M. W. and Duggin, G. G. (1978). Covalent binding of metabolites of acetaminophen to kidney protein and depletion of renal glutathione. J. Pharmacol. exptl. Ther., 206, 218–26Google Scholar
  81. Nachtomi, E. (1970). The metabolism of ethylene dibromide in the rat: the enzymic reaction with glutathione in vitro and in vivo. Biochem. Pharmacol., 19, 2853–60PubMedCrossRefGoogle Scholar
  82. Nachtomi, E., Alumot, E. and Bondi, A. (1966). The metabolism of ethylene dibromide in the rat. I. Identification of detoxication products in urine. Isr. J. Chem., 4, 239–46CrossRefGoogle Scholar
  83. Nachtomi, E., Alumot, E. and Bondi, A. (1968). Biochemical changes in organs of chicks and rats poisoned with ethylene dibromide and carbon tetrachloride. Isr. J. Chem., 6, 803–11CrossRefGoogle Scholar
  84. Nash, J. A., King, L. J., Lock, E. A. and Green, T. (1984). The metabolism and disposition of hexachloro-1,3-butadiene in the rat and its relevance to nephrotoxicity. Toxicol. appl. Pharmacol., 73, 124–37PubMedCrossRefGoogle Scholar
  85. Odum, J. and Green, T. (1984). The metabolism and nephrotoxicity of tetrafluoro-ethylene in the rat. Toxicol. appl. Pharmacol., 76, 306–18PubMedCrossRefGoogle Scholar
  86. Oesch, F. and Wolf, C. R. (1986). Properties of the microsomal glutathione trans-ferases involved in hexachlorobutadiene and chloro-2,4-dinitrobenzene conjugation. Mol. Pharm., in pressGoogle Scholar
  87. Olmstead, E. V. (1960). Pathological changes in ethylene dibromide poisoning. Arch. Ind. Hlth., 21, 525–9Google Scholar
  88. Ozawa, N. and Guengerich, F. P. (1983). Evidence for formation of an S-[2-(N7-guanyl)ethyl] glutathione adduct in glutathione-mediated binding of the carcinogen 1,2-dibromoethane to DNA. Froc. Nat. Acad. Sci., 80, 5266–70CrossRefGoogle Scholar
  89. Parker, V. H. (1965). A biochemical study of the toxicity of S-dichlorovinyl-L-cysteine. Fd Cosmet. Toxicol., 3, 75–84CrossRefGoogle Scholar
  90. Potter, C. L., Gandolfi, A. J., Nagle, R. and Clayton, J. W. (1981). Effects of inhaled chlorotrifluoroethylene and hexafluoropropene on the rat kidney. Toxicol. appl. Pharmacol., 59, 431–40PubMedCrossRefGoogle Scholar
  91. Pratt, I. S., Ormond, T. and Lock, E. A. (1986). Metabolism of the mercapturic acid of hexachloro-1,3-butadiene by rat kidney cytosol in vitro. In abstracts. 27th Congress European Soc. Toxicology, Harrogate, UK, 27th-29th MayGoogle Scholar
  92. Rafter, J. J., Bakke, J., Larsen, G., Gustafsson, B. and Gustafsson, J-A. (1983). Role of the intestinal microflora in the formation of sulphur containing conjugates of xenobiotics. Rev. Biochem. Toxicol., 5, 387–408Google Scholar
  93. Rankin, B. B. and Curthoys, N. P. (1982). Evidence for the renal paratubular transport of glutathione. Febs. Lett., 147, 193–6PubMedCrossRefGoogle Scholar
  94. Rannug, U. and Beije, B. (1979). The mutagenic effect of 1,2-dichloroethane on Salmonella Typhimurium: II. Activation by the isolated perfused rat liver. Chem. Biol. Interac., 24, 265–85CrossRefGoogle Scholar
  95. Rannug, U., Sundvall, A. and Ramel, C. (1978). The mutagenic effect of 1,2-dichloroethane on Salmonella Typhimurium: I. Activation through conjugation with glutathione in vitro. Chem. Biol. Interac., 20, 1–16CrossRefGoogle Scholar
  96. Reed, D. J. and Ellis, W. W. (1981). Influence of gamma-glutamyl transpeptidase inactivation on the status of extracellular glutathione and glutathione conjugates. Adv. Exp. Med. Biol, 136 Pt. A, 75–86Google Scholar
  97. Reichert, D., Schutz, S. and Metzler, M. (1985). Excretion pattern and metabolism of hexachlorobutadiene in rats: evidence for metabolic activation by conjugation reactions. Biochem. Pharmacol, 34, 399–405CrossRefGoogle Scholar
  98. Roch-Ramel, F. and Weiner, I. M. (1980). Renal urate excretion: factors determining the action of drugs. Kidney Int., 18, 665–76PubMedCrossRefGoogle Scholar
  99. Roch-Ramel, F., White, F., Vowels, L., Simmonds, H. A. and Cameron, J. S. (1980). Micropuncture study of tubular transport of urate and PAH in the pig kidney. Am. J. Physiol, 239, F107–F112Google Scholar
  100. Ross, B. D. and Guder, W. G. (1982). Heterogeneity and compartmentation in the kidney. In: Metabolic Compartmentation (ed. H. Sies), Academic Press, London, pp. 363–429Google Scholar
  101. Rowe, V. K., Spencer, H. C, McCollister, D. D., Hollingsworth, R. L. and Adams, E. M. (1952). Toxicity of ethylene dibromide determined on experimental animals. Arch. Ind. Hyg. Occup. Med., 6, 158–73Google Scholar
  102. Rush, G. F., Smith, J. H., Newton, J. F. and Hook, J. B. (1984). Chemically induced nephrotoxicity: role of metabolic activation. CRC. Crit. Rev. Toxicol, 13, 99–160CrossRefGoogle Scholar
  103. Saari, J. C. and Schultze, M. O. (1965). Cleavage of S-(l,2-dichlorovinyl)-L-cysteine by Escherichia Coli B. Archs. Biochem. Biophys., 109, 595–602CrossRefGoogle Scholar
  104. Sakharova, L. N. and Tolgskaya, M. S. (1977). Toxicity and nature of the effect of some halo derivatives of ethylene-difluoro-dichloroethylene, trifluorochloro-ethylene and tetrafluoroethylene. Gig. Tr. Zabol., 5, 36–42Google Scholar
  105. Schasteen, C. S. and Reed, D. J. (1983). The hydrolysis and alkylation activities ofGoogle Scholar
  106. S-(2-haloethyl)-L-cysteine analogs — evidence for extended half-life. Toxicol. appl. Pharmacol., 70, 423–32Google Scholar
  107. Schnellmann, R. G., Lock, E. A. and Mandel, L. J. (1986). A mechanism of S-(1,1,2,3,4-pentachloro-1,3-butadienyl)-L-cysteine (PCBC) toxicity to rabbit proximal tubules (RPT). Toxicologist, 6, 176Google Scholar
  108. Schultze, M. O., Klubes, P., Perman, V., Mitzuno, N. S., Bates, F. W. and Sautter, J. H. (1959). Blood dyscrasia in calves by S-(dichlorovinyl)-L-cysteine. Blood, 14, 1015–25PubMedGoogle Scholar
  109. Schultze, M. O., Derr, R. F., Mizuno, N. S., Joel, D. D. and Sautter, J. H. (1962). Effect of phenylalanine on toxicity of S-(dichlorovinyl)-L-cysteine in the rat and calf. Proc. exptl. Biol. Med., 111, 499–502CrossRefGoogle Scholar
  110. Shih, T-W and Hill, D. L. (1981). Metabolic activation of 1,2-dibromoethane by glutathione transferase and by microsomal mixed function oxidase: further evidence for formation of two reactive metabolites. Res. Commun. Chem. Path. Pharm., 33, 449–61PubMedGoogle Scholar
  111. Smith, A. G. and Francis, J. (1983). Evidence for the active renal secretion of S-pentachlorophenyl-N-acetyl-L-cysteine by female rats. Biochem. Pharmacol., 32, 3797–801PubMedCrossRefGoogle Scholar
  112. Smith, J. H. and Hook, J. B. (1984). Mechanism of chloroform nephrotoxicity III. Renal and hepatic microsomal metabolism of chloroform in mice. Toxicol. appl. Pharmacol., 73, 511–24PubMedCrossRefGoogle Scholar
  113. Spencer, H. C, Rowe, V. K., Adams, E. M., McCollister, D. D. and Irish, D. D. (1951). Vapour toxicity of ethylene dichloride determined by experiments on laboratory animals. Arch. Ind. Hyg. Occup. Med., 4, 482–93Google Scholar
  114. Stevens, J. L. (1985a). Isolation and characterisation of a rat liver enzyme with both cysteine conjugate β-lyase and kynureninase activity. J. Biol Chem., 260, 7945–50PubMedGoogle Scholar
  115. Stevens, J. L. (1985b). Cysteine conjugate β-lyase activities in rat kidney cortex: subcellular localisation and relationship to the hepatic enzyme. Biochem. Biophys. Res. Commun., 129, 499–504Google Scholar
  116. Stevens, J. L. and Jakoby, W. B. (1983). Cysteine conjugate β-lyase. Mol. Pharm., 23, 761–5Google Scholar
  117. Stonard, M. D. (1973). Further studies on the site and mechanism of action of S-(l,2-dichlorovinyl)-L-cysteine and S-(l,2- dichlorovinyl)-3-mercaptopropionic acid in rat liver. Biochem. Pharmacol, 22, 1329–35PubMedCrossRefGoogle Scholar
  118. Stonard, M. D. and Parker, V. H. (1971a). 2-oxoacid dehydrogenases of rat liver mitochondria as the site of action of S-(l,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)-3-mercaptopropionic acid. Biochem. Pharmacol., 20, 2417–27PubMedCrossRefGoogle Scholar
  119. Stonard, M. D. and Parker, V. H. (1971b). Metabolism of S-(l,2-dichlorovinyl)-L-cysteine by rat liver mitochondria. Biochem. Pharmacol, 20, 2429–37PubMedCrossRefGoogle Scholar
  120. Sundheimer, D. W., White, R. D., Brendel, K. and Sipes, I. G. (1982). The bio-activation of 1,2-dibromoethane in rat hepatocytes: covalent binding to nucleic acids. Carcinogenesis, 3, 1129–33PubMedCrossRefGoogle Scholar
  121. Tate, S. S. (1980). Enzymes of mercapturic acid formation. In: Enzymatic Basis of Detoxication Vol. II (ed. W. B. Jakoby), Academic Press, New York, pp. 95–120Google Scholar
  122. Tateishi, M., Suzuki, S. and Shimizu, H. (1978). Cysteine conjugate β-lyase in rat liver. J. Biol. Chem., 253, 8854–9PubMedGoogle Scholar
  123. Terracini, B. and Parker, V. H. (1965). A pathological study on the toxicity of S-dichlorovinyl-L-cysteine. Fd Cosmet. Toxicol, 3, 67–74CrossRefGoogle Scholar
  124. Tisher, C. A. (1976). Anatomy of the kidney. In: The Kidney (eds B. M. Brenner and F C. Rector), Saunders, Philadelphia, pp. 3–64Google Scholar
  125. Tomisawa, H., Suzuki, S., Shigeyasa, I., Fukazawa, H. and Tateishi, M. (1984). Purification and characterisation of C-S lyase from Fusobacterium varium. J. Biol. Chem., 259, 2588–93PubMedGoogle Scholar
  126. Trump, B. F., Berezesky, I. K., Lipsky, M. M. and Jones, T. W. (1985). Heterogeneity of the nephron: significance to nephrotoxicity. In: Renal Heterogeneity and Target Cell Toxicity (eds P. H. Bach and E. A. Lock), John Wiley, Chichester, pp. 31–42Google Scholar
  127. Tune, B. M., Burge, M. B. and Patlak, C. S. (1969). Characteristics of p-amino-hippurate transport in proximal renal tubule. Am. J. Physiol., 217, 1057–63PubMedGoogle Scholar
  128. Vadi, H. V., Schasteen, C. S. and Reed, D. J. (1985). Interactions of S-(2-halo-ethyl)-mercapturic acid analogs with plasmid DNA. Toxicol appl. Pharmacol., 80, 386–96PubMedCrossRefGoogle Scholar
  129. Valtin, H. (1973). Renal Function: Mechanisms Preserving Fluid and Solute Balance in Health, Little, Brown, BostonGoogle Scholar
  130. Van Bladeren, P. J., Breimer, D. D., Rotteveel-Smijs, G. M. T., De Jong, R. A. W., Buijs, W., Van Der Gen, A. and Mohn, G. R. (1980). The role of glutathione conjugation in the mutagenicity of 1,2-dibromoethane. Biochem. Pharmacol, 29, 2975–82PubMedCrossRefGoogle Scholar
  131. Venkatchalam, M. A., Bernard, D. B., Donohoe, J. F. and Levinsky, N. G. (1978). Ischemic damage and repair in the rat proximal tubule: differences among the SI, S2 and S3 segments. Kidney Int., 14, 31–49CrossRefGoogle Scholar
  132. Wachsmuth, E. D. (1985). Renal heterogeneity at a light microscopic level. In: Renal Heterogeneity and Target Cell Toxicity (eds P. H. Bach and E. A. Lock), John Wiley, Chichester, pp. 13–30Google Scholar
  133. Wallach, D. P. (1961). Studies on the GABA pathway I. The inhibition of γ-amino-butyric acid-α-ketoglutaric acid transaminase in vitro and in vivo by U-7524 (amino-oxyacetic acid). Biochem. Pharmacol., 5, 323–31PubMedCrossRefGoogle Scholar
  134. Walther, A., Fischer, H. D., Jaeger, J., Kemmer, C. and Kunze, D. (1969). Biochemical and morphological studies on the toxicity of chlorotrifluoroethylene. Acta Biol. Med. Ger., 23, 685–706PubMedGoogle Scholar
  135. Weisiger, R. A. and Jakoby, W. B. (1980). S-methylation: thiol S-rnethyl-transferase. In: Enzymatic Basis of Detoxication, Vol. II (ed. W. B. Jakoby), Academic Press, New York, pp. 131–140Google Scholar
  136. Wolf, C. R., Berry, P. N., Nash, J. A., Green, T. and Lock, E. A. (1984). The role of microsomal and cytosolic glutathione-S-transferases in the conjugation of hexachloro-1,3-butadiene and its possible relevance to toxicity. J. Pharmacol. exptl. Ther., 228, 202–8Google Scholar
  137. Zenser, T. V., Mattammal, M. B. and Davis, B. B. (1978). Differential distribution of the mixed function oxidase activities in rabbit kidney. J. Pharmacol. exptl. Ther., 207, 19–25Google Scholar

Copyright information

© Edward A. Lock 1987

Authors and Affiliations

  • Edward A. Lock

There are no affiliations available

Personalised recommendations