The Kidney as a Target for Biological Reactive Metabolites

Linking Metabolism to Toxicity
  • Terrence J. Monks
  • Maria I. Rivera
  • Jos J. W. M. Mertens
  • Melanie M. C. G. Peters
  • Serrine S. Lau
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 387)


The conjugation of potentially toxic electrophiles with glutathione (GSH), the process of thioether formation, is usually associated with detoxication and excretion (Sies and Ketterer, 1988). Compounds that are conjugated with GSH are usually excreted in urine as their corresponding mercapturic acids, S-conjugates of N-acetylcysteine. The kidney is susceptible to chemical induced injury, and GSH conjugation seems to play a major role in the bioactivation of many of renal toxicants. Halogenated alkanes and alkenes are targeted to the kidney via GSH conjugation, and subsequent bioactivation of the corresponding cysteine conjugate by cysteine conjugate β-lyase (Dekant et al., 1994). Polyphenols also seem to be targeted to the kidney via extra-renal conjugation with GSH (Monks and Lau 1994a) and tissue selectivity in this instance appears to be conferred by the high activity of γ-glutamyl transpeptidase on the brush border membrane of renal proximal tubular epithelial cells. Thus, in contrast to the generally accepted role of GSH conjugation serving as a detoxication mechanism conjugation of quinones with GSH results in the formation of potent, and selective, nephrotoxicants (Monks et al., 1985, 1988; Lau et al., 1988, 1990; Mertens et al., 1991), and evidence has accumulated suggesting that GSH conjugation of quinones may be a common mechanism of bioactivation (Monks and Lau, 1992).


Brush Border Membrane Glutathione Conjugate Mercapturic Acid Buthionine Sulfoximine Cysteine Conjugate 
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. Ahnström, G., and Ljungman, M. (1988) Effects of 3-aminobenzamide on the rejoining of DNA-strand breaks in mammalian cells exposed to methyl methanesulphonate; Role of poly(ADP-ribose) polymerase. Mutat.Res. 194, 17–22.PubMedCrossRefGoogle Scholar
  2. Albuquerque, S.J., Monks, T.J. and Lau, S.S. (1995) Modulation of intracellular pH by 2-bromo-6-glutathion-S-yl-hydroquinone. Toxicologist, 15, 305 (Abstract).Google Scholar
  3. Andreoli, S., and McAteer, J.A. (1990) Reactive oxygen molecule mediaed injury in endothelial and renal tubular epithelial cells in vitro. Kidney Int. 38, 785–794.PubMedCrossRefGoogle Scholar
  4. Berger, N.A. (1985) Symposium: Cellular response to DNA damage; The role of poly(ADP-ribose). Poly(ADP-ribose) in the cellular response to DNA damage. Rad. Res. 101, 4–15.CrossRefGoogle Scholar
  5. Birnboim, H.C. (1986) DNA strand breaks in human leukocytes induced by Superoxide anion, hydrogen peroxide and tumor promoters are repaired slowly compared to breaks induced by ionizing radiation. Carcinogenesis 7, 1511–1517.PubMedCrossRefGoogle Scholar
  6. Boobis, A.R., Fawthrop, D.J., and Davies, D.S. (1989). Mechanisms of cell death. TIPS, 10, 275–280.PubMedGoogle Scholar
  7. Brown, P.C., Dulik, D.M., and Jones, T.W. (1991) The toxicity of menadione (2-methyl-l,4-naphthoquinone) and two thioether conjugates studied with isolated renal epithelial cells. Arch. Biochem. Biophys., 285, 187–196.PubMedCrossRefGoogle Scholar
  8. Bursch, W., Oberhammer, F., and Schulte-Hermann, R.(1992). Cell death by apoptosis and its protective role against disease. TIPS, 13, 245–251.PubMedGoogle Scholar
  9. Canales, P.L., Kleiner, H.E., Monks, T.J., and Lau, S.S. (1993) Formation of 8-hydroxydeoxygaunonsine by quinol-thioethers. Toxicologist, 13, 202 (Abstr).Google Scholar
  10. Cleaver, J.E., and Morgan, W.F. (1985) Poly(ADP-ribose) synthesis is involved in the toxic effects of alkylating agents but does not regulate DNA repair. Mutation Res. 150, 69–76.PubMedCrossRefGoogle Scholar
  11. Dekant, W., Vamvakas, S. and Anders, M.W. (1994) Formation and fate of nephrotoxic and cytotoxic glutathione S-conjugates: Cysteine conjugate β-lyase pathway. In: Conjugation-Dependent Carcinogemcity and Toxicity of Foreign Compounds. (M.W. Anders and W. Dekant, Eds.) pp. 115–162, Academic Press, San Diego CA.Google Scholar
  12. DcMello Filho, A.C., Hoffmann, M.E., and Meneghini, R. (1984) Cell killing and DNA damage by hydrogen peroxide are mediated by intracellular iron. Biochem. J. 218, 273–275.Google Scholar
  13. DcMello Filho, A.C. and Meneghini, R. (1984) In vivo formation of single-strand breaks in DNA by hydrogen peroxide is mediated by the Haber-Weiss reaction. Biochim. Biophys. Ada 781, 56–63.CrossRefGoogle Scholar
  14. Dizdaroglu, M., Nackerdien, Z., Chao, B-C, Gajewski, E., and Rao, G. (1991) Chemical nature of in vivo DNA base damage in hydrogen peroxide treated mammalian cells. Arch. Biochem. Biophys. 285, 388–390.PubMedCrossRefGoogle Scholar
  15. Djuric, Z., Everett, C.K. and Luongo, D. (1993) Toxicity, single-strand breaks, and 5-hydroxymethyl-2’-deoxyuridine formation in human breast epithelial cells treated with hydrogen peroxide. Free Rad. Biol. Med. 14, 541–547.PubMedCrossRefGoogle Scholar
  16. Eckert, K.-G., Eyer, P., Sonnenbichler, J. and Zetl, I. (1990a) Activation and detoxication of aminophenols. II. Synthesis and structural elucidation of various thiol addition products of 1,4-benzoquinoneimine and N-acetyl-l,4-benzoquinoneimine. Xenobiotica, 20, 333–350.PubMedCrossRefGoogle Scholar
  17. Eckert, K.-G., Eyer, P., Sonnenbichler, J. and Zetl, I. (1990b) Activation and detoxication of aminophenols. III. Synthesis and structural elucidation of various glutathione addition products to 1,4-benzoquinone. Xenobiotica, 20, 351–361.PubMedCrossRefGoogle Scholar
  18. Fowler, L.M., Moore, R.D., Foster, J.R., and Lock, E.A (1991) Nephrotoxicity of 4-aminophenol glutathione conjugate. Human Expt. Toxicol, 10, 451–459.CrossRefGoogle Scholar
  19. Fowler, L.M., Foster, J.R., and Lock, E.A (1993) The effect of ascorbic acid, acivicin and probenecid on the nephrotoxicity of 4-aminophenol in the Fischer 344 rat. Arch. Toxicol., 67, 613–621.PubMedCrossRefGoogle Scholar
  20. Gaal, J.C., Smith, K.R., and Pearson, C.K. (1987) Cellular euthanasia mediated by a nuclear enzyme: A central role for nuclear ADP-ribosylation in cellular metabolism. Trends in Biochem. Sci. 12, 129–130.CrossRefGoogle Scholar
  21. Gartland, K.P.R., Bonner, F.W., Timbrell, J.A., and Nicholson, J.K. (1989) Biochemical characterization of 4-aminophenol-induced nephrotoxic lesions in the F344 rat. Arch. Toxicol., 63, 97–106, 1989.PubMedCrossRefGoogle Scholar
  22. Green, C.R., Ham, K.N., and Tange, J.D (1969) Kidney lesions induced in rats by 4-aminophenol. Br. Med. J., 1, 162–164.PubMedCrossRefGoogle Scholar
  23. Hackenbrock, C.R. (1966). Ultrastructural basis for metabolically linked mechanical activity in mitochondria. I. Reversible ultrastructural changes with change in metabolic steady state in isolated liver mitochondria. J. Cell Biol, 30, 269–297.PubMedCrossRefGoogle Scholar
  24. Hirose, M., Inoue, T., Masuda, A., Tsuda, H., and Ito, N (1987) Effects of simultaneous treatment with various chemicals on BHA-induced development of rat forestomatch hyperplasia. Complete inhibition by diethylmaletate in a 5-week feeding study. Carcinogenesis, 8, 1555–1558.PubMedCrossRefGoogle Scholar
  25. Hill, B.A., Heather, H.K., Ryan, E.A., Dulik, D.M., Monks, T.J. and Lau, S.S. (1993) Identification of multi-S-substituted conjugates of hydroquinone by HPLC-coulometric electrode array analysis and mass spectroscopy. Chem Res. Toxicol. 6, 459–469.PubMedCrossRefGoogle Scholar
  26. Hill, B.A., Monks T.J., and Lau S.S. (1992). The effects of 2,3,5-(triglutathion-S-yl)hydro-quinone on renal mitochondrial respiratory function in vivo and in vitro: Possible role in cytotoxicity. Toxicol. Appl. Pharmacol, 117, 165–171.PubMedCrossRefGoogle Scholar
  27. Imlay, J.A. and Linn, S. (1988) DNA damage and oxygen radical toxicity. Science 240, 1302–1309.PubMedCrossRefGoogle Scholar
  28. James, M.R. and Lehman, A.R.(1982) Role of poly(adenosine diphosphate ribose) in deoxyribonucleic acid repair in human fibroblasts. Biochemistry 21, 4007–4013.PubMedCrossRefGoogle Scholar
  29. Jeong, J.K., Stevens, J.L., Lau, S.S., and Monks, T.J. (1994) Gene expression in response to quinone-thioethers in LLC-PK1 cells. Toxicologist, 14, 180 (Abstract).Google Scholar
  30. Kari, F.W., Bucher, J., Eustis, S.L., Haseman, J.K., and Huff, J.E (1992) Toxicity and carcinogenicity of hydroquinone in F344/N rats and B6C3F1 mice. Food Chem. Tox., 30, 737–747.CrossRefGoogle Scholar
  31. Klos, C, Koob, M., Kramer, C, and Dekant, W. (1992) p-Aminophenol nephrotoxicity: Biosynthesis of toxic glutathione conjugates. Toxicol. Appl. Pharmacol., 115, 98–106.PubMedCrossRefGoogle Scholar
  32. Kvietys, P.R., Inauen, W., Bacon, B.R., and Grisham, M.B. (1989) Xanthine oxidase-induced injury to endothelium: Role of intracellular iron and hydroxyl radical. Am. J. Physiol. 257, H1640–H1646.PubMedGoogle Scholar
  33. Lau, S.S., Hill, B.A., Highet, R.J., and Monks, T.J. (1988) Sequential oxidation and glutathione addition to 1,4-benzoquinone: Correlation of toxicity with increased glutathione substitution. Molec. Pharmacol. 34, 829–836.Google Scholar
  34. Lau, S.S., Jones, T.W., Highet, R.J., Hill, B.A. and Monks, T.J (1990) Differences in the localization and extent of the renal proximal tubular necrosis caused by mercapturic acid and glutathione conjugates of menadione and 1,4-naphthoquinone. Toxicol. Appl. Pharmacol., 104, 334–350.PubMedCrossRefGoogle Scholar
  35. Lau, S.S., Peters, M.M., Meussen, E., Rivera, M.I., Jones, T.W., van Ommen, B., van Bladeren, P.J., and Monks, T.J. (1994) Nephrotoxicity of 2-tert-butyl-hydroquinone glutathione conjugates. Toxicologist, 14, 180 (Abstract).Google Scholar
  36. Leanderson, P. and Tagesson, C. (1992) Cigarette smoke-induced DNA damage in cultured human lung cells: Role of hydroxyl radicals and endonuclease activation. Chem. Biol. Int. 81, 197–208.CrossRefGoogle Scholar
  37. Lunte, S.M. and Kissinger, P.T (1983) Detection and identification of sulfhydryl conjugates of p-benzoquinone in microsomal incubations of benzene and phenol. Chem. Biol. Int., 47, 195–212.CrossRefGoogle Scholar
  38. Mertens, J.J.W.M., Gibson, N.W., Lau, S.S. and Monks, T.J. Reactive oxygen species and DNA damage in 2-bromo-(glutathion-S-yl)hydroquinone mediated cytotoxicity. Arch. Biochem. Biophys. 47 197 1995.Google Scholar
  39. Mertens, J.J.W.M., Temmink, J.H.M., van Bladeren, P.J., Jones, T.W., Lo, H.-H., Lau, S.S., and Monks, T.J (1991) Inhibition of y-glutamyl transferase potentiates the nephrotoxicity of glutathione conjugated chlorohydroquinones. Toxicol. Appl. Pharmacol., 110, 45–60.PubMedCrossRefGoogle Scholar
  40. Monks, T.J. and Lau, S.S. (1990) Glutathione conjugation, y-glutamyl transpeptidase and the mercapturic acid pathway as modulators of 2-bromohydroquinone oxidation. Toxicol. Appl. Pharmacol., 103, 557–563. 1990.PubMedCrossRefGoogle Scholar
  41. Monks, T.J. and Lau, S.S. (1992) Toxicology of quinone-thioethers. CRC Crit. Rev. Tox. 22, 243–270.CrossRefGoogle Scholar
  42. Monks, T.J. and Lau, S.S. (1994a) Glutathione conjugation as a mechanism for the transport of reactive metabolites. In: Conjugation-Dependent Carcinogenicity and Toxicity of Foreign Compounds. (M.W. Anders and W. Dekant, Eds.) pp. 183–210, Academic Press, San Diego CA.Google Scholar
  43. Monks, T.J. and Lau, S.S. (1994b) Glutathione conjugate mediated toxicities. In: Handbook of Experimental Pharmacology, Vol. 112: Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity. (Kauffman, F.C., Ed.) pp. 459–509, Springer Verlag, Berlin Heidelberg.CrossRefGoogle Scholar
  44. Monks, T.J., Lau, S.S., Highet, R.J. and Gillette, J.R. (1985) Glutathione conjugates of 2-bromohydroquinone are nephrotoxic. Drug Metab. Dispos. 13, 553–559.PubMedGoogle Scholar
  45. Monks, T.J., Highet, R.J. and Lau, S.S. (1988) 2-Bromo-(diglutathion-S-yl)hydroquinone nephrotoxicity: Physiological, biochemical and electrochemical determinants. Molec. Pharmacol. 34, 492–500.Google Scholar
  46. Nduka, N., Skidmore, C.J., and Shall, S. (1980) The enhancement of cytotoxicity of Af-methyl-TV-nitrosourea and of γ-irradiation by inhibition of poly(ADP-ribose) polymerase. Eur. J. Biochem. 105, 525–530.PubMedCrossRefGoogle Scholar
  47. Nerland, D.E. and Pierce, W.M (1990) Identification of N-acetyl-S-(2,5-dihydroxyphenyl)-L-cysteine as a urinary metabolite of benzene, phenol, and hydroquinone. Drug Metab. Disp., 18, 958–961.Google Scholar
  48. Newton, J.F., Kuo C.-H., Gemborys, M.W., Mudge, G.H., and Hook, J.B (1982) Nephrotoxicity of 4-aminophenol, a metabolite of acetaminophen in the F344 rat. Toxicol. Appl. Pharmacol., 65, 336–344.PubMedCrossRefGoogle Scholar
  49. Peters, M.M.C.G., Jones, T.W., Monks, T.J., and Lau, S.S. (1995) Cytotoxicity and cell proliferation induced by the nephrocarcinogen hydroquinone and its tri-glutathionyl metabolite. Toxicologist, 15, 231 (Abstract).Google Scholar
  50. Purnell, M. and Whish, W.J.D. (1980) Novel inhibitors of poly(ADP-ribose)synthetase. Biochem. J. 185, 775–777.PubMedGoogle Scholar
  51. Rao, D.N.R., Takahashi, N., and Mason, R.P. (1988) Characterization of a glutathione conjugate of the 1,4-benzosemiquinone-free radical formed in rat hepatocytes. J Biol Chem 263: 17981–17986.PubMedGoogle Scholar
  52. Reimer, K.A., Ganote, C.E., and Jennings, R.B. (1972). Alterations in renal cortex following ischemic injury. III. Ultrastructure of proximal tubules after ischemia or autolysis. Lab. Invest. 26, 347–363.PubMedGoogle Scholar
  53. Rivera, M.I., Jones, T.W., Lau, S.S. and Monks, T.J (1994) Early morphological and biochemical changes during 2-bromo-(diglutathion-S-yl)hydroquinone-induced nephrotoxicity. Toxicol. Appl. Pharm., 128, 239–250.CrossRefGoogle Scholar
  54. Sawahata, T. and Neal, R.A (1983) Biotransformation of phenol to hydroquinone and catechol by rat liver microsomes. Molec. Pharmacol, 23, 453–460.Google Scholar
  55. Schilderman, P.A.E.L., van Maanen, J. M. S., Smeets, E.J., ten Hoor, F., and Kleinjans, J. C. S (1993) Oxygen radical formation during prostaglandin H synthase-mediated biotransformation of butylated hydroxyanisole. Carcinogenesis, 114, 347–353.CrossRefGoogle Scholar
  56. Schraufstatter, I.U., Hinshaw, D.B., Hyslop, P.A., Spragg, R.G., and Cochrane, CG (1986) Oxidant injury of cells. DNA strand-breaks activate polyadenosine diphosphate-ribose polymerase and lead to depletion of nicotinamide adenine dinucleotide. J. Clin. Invest., 77, 1312–1320.PubMedCrossRefGoogle Scholar
  57. Seto, S., Carrera, C.J., Kubota, M., Wasson, D.B., Carson, D.A. (1985) Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J. Clin. Invest. 75, 377–383.PubMedCrossRefGoogle Scholar
  58. Shen, W., Kamendulis, M., Ray, S.D., and Corcoran, G.B. (1992) Acetaminophen-induced cytotoxicity in cultured mouse hepatocytes: Effects of Ca2+-endonuclease, DNA repair, and glutathione depletion inhibitors on DNA fragmentation and cell death. Toxicol. Appl. Pharmacol. 112, 32–40.PubMedCrossRefGoogle Scholar
  59. Shibata, M-A., Hirose, M. Tanaka, H., Asakawa, E., Shirai, T., and Ito, N. (1991) Induction of renal cell tumors in rats and mice, and enhancement of hepatocellular tumor development in mice after long-term hydroquinone treatment, Jpn. J. Cancer Res., 82, 1211–1219.PubMedCrossRefGoogle Scholar
  60. Sies H, and Ketterer, B. (1988) Glutathione conjugation: Mechanisms and biological significance, Academic Press, San Diego, CA.Google Scholar
  61. Sun, Y. Pommier, Y. Colburn, N.H. (1992) Acquisition of a growth inhibitory response to phorbol esters involves DNA damage. Cancer Res. 52, 1907–1915.PubMedGoogle Scholar
  62. Tajima, K., Hashizaki, M., Yamamoto, K., and Mizutani, T (1991) Identification and structure characterization of S-containing metabolites of 3-tert-butyl-4-hydroxyanisole in rat urine and liver microsomes. Drug Metab. Disp., 19, 1028–1033.Google Scholar
  63. Takahashi, N., Schreiber, J., Fischer, V., and Mason, R.P. (1987) Formation of glutathione-conjugated semiquinones by the reaction of quinones with glutathione: An ESR study. Arch Biochem Biophys 252: 41–48.PubMedCrossRefGoogle Scholar
  64. Tanizawa, A., Kubota, M., Takimoto, T., Akiyama, Y, Seto, S., Kiriyama, Y, and Mikawa, H. (1987) Prevention of adriamycin-induced interphase death by 3-aminobenzamide and nicotinamide in a human premyelocytic leukemia cell line. Biochem. Biophys. Res. Communications 144, 1031–1036.CrossRefGoogle Scholar
  65. Trump, B.F., Goldblatt, P.J., and Stowell, R.E. (1965). Studies on necrosis of mouse liver in vitro: Ultrastructural alterations in the mitochondria of hepatic parenchymal cells. Lab. Invest. 14, 343–371.PubMedGoogle Scholar
  66. Tsuda, H., Fukushima, S., Imaida, K., Sakata, T., and Ito, N (1984) Modification of carcinogenesis by antioxidants and other compounds. Acta. Pharmacol. Toxicol., 55, 125–143.CrossRefGoogle Scholar
  67. Tunek, A., Platt, K.L., Pryzbylski, M., and Oesch, F (1980) Multi-step metabolic activation of benzene. Effect of Superoxide dismutase on covalent binding to microsomal macromolecules, and identification of glutathione conjugates using high pressure liquid chromatography and field desorption mass spectrometry. Chem. Biol. Int., 33, 1–17.CrossRefGoogle Scholar
  68. Tzagoloff, A. (1982). Mitochondria, p. 17. Plenum Press, New York.Google Scholar
  69. Walker, P.D. and Shah, S.H. (1991) Hydrogen peroxide cytotoxicity in LLC-PK1 cells: A role for iron. Kidney Int. 40, 891–898.PubMedCrossRefGoogle Scholar
  70. Wefers, H. and Sies, H (1983) Hepatic low-level chemiluminesence during redox cycling of menadione and the menadione-glutathione conjugate: Relation to glutathione and NAD(P)H: Quinone reductase (DT-diaphorase) activity. Arch. Biochem. Biophys., 224, 568–578.PubMedCrossRefGoogle Scholar
  71. Wolf, S.P., and Spector, A. (1987). Pro-oxidant activation of ocular reductants. II. Lens epithelial cell cytotoxicity of a dietary quinone is associated with a stable free radical formed with glutathione in vitro. Exp. Eye Res. 45, 791–801.CrossRefGoogle Scholar
  72. Wyllie, A.H., Kerr, J.F.R., and Currie, A.R. (1980). Cell death: The significance of apoptosis. Int. Rev. Cytol. 68, 251–306.PubMedCrossRefGoogle Scholar
  73. Zwelling, L.A., Kerrigan, D., and Pommier, Y. (1982) Inhibition of poly-(adenosine diphosphoribose) synthesis slows the resealing rate of X-ray induced DNA strand breaks. Biochem. Biophys. Res. Comm. 104, 897–902.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Terrence J. Monks
    • 1
  • Maria I. Rivera
    • 1
  • Jos J. W. M. Mertens
    • 1
  • Melanie M. C. G. Peters
    • 1
  • Serrine S. Lau
    • 1
  1. 1.Division of Pharmacology and Toxicology College of PharmacyUniversity of Texas at AustinAustinUSA

Personalised recommendations