Skip to main content
SpringerLink
Log in

Combined effects of cadmium and nickel on testicular xenobiotic metabolizing enzymes in rats

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

When male rats were given a single dose of cadmium (Cd) (3.58 mg CdCl2·H2O/kg, ip) 72 hr prior to sacrifice, the testicular 7-ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST) activities toward the substrates 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (EPNP), and cumene hydroperoxide (CHPx) decreased significantly as compared to controls. Cd also inhibited reduced glutathione (GSH) level while increasing the lipid peroxidation (LP) level significantly. When the animals were given a single dose of nickel (Ni) (59.5 mg NiCl2·6H2O/kg, ip) 16 hr prior to sacrifice, significant decreases were observed in EROD and GST activities toward CDNB, EAA, EPNP, and CHPx, and GSH level. No significant alterations were noted in DCNB GST activity and LP level by Ni. For the combined treatment, rats received the single dose of Ni 56 hr after the single dose of Cd and were killed 16 hr later. In these animals, lesser depressions were observed on EROD activity and LP level than those of Cd alone. The combination of metals significantly inhibited GST activities and GSH level but not to a greater degree than noted by Cd or Ni alone. Plasma testosterone levels of Cd-, Ni-, and combination-treated rats decreased significantly compared to controls. The strongest depression was achieved by Cd alone. Cd, both alone and in combination with Ni, increased the tissue Ni uptake significantly. Ni, however, did not produce such an effect on the tissue uptake of Cd in either case. Cd treatment caused interstitial edema and coagulation necrosis in seminiferous tubules and also caused fibrinoidal necrosis in vascular endothelium. Ni treatment did not produce any pathological testicular alterations compared to controls. Combined treatment produced fewer pathological alterations (i.e., only interstitial edema) than that of Cd treatment. These results reveal that the combination of Cd and Ni does not have a synergistic effect on testicular xenobiotic metabolizing enzymes, and in contrast, Ni has an ameliorating effect on pathological disturbances caused by Cd alone in the rat testis.

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

  1. P. B. Hammond and R. P. Beliles, Metals, in Toxicology, J. Doull, C. D. Klaassen, and M. O. Amdur, eds., Macmillan, New York, pp. 409–467 (1980).

    Google Scholar 

  2. A. Léonard, G. B. Gerber, and P. Jacquet, Carcinogenicity, mutagenicity and teratogenicity of Ni, Mutat. Res. 87, 1–15 (1981).

    PubMed  Google Scholar 

  3. K. S. Kasprzak, Nickel, in Advances in Modern Environmental Toxicology, L. Fishbein, A. Furst, and M. A. Mechlman, eds., Princeton University Press, Princeton, NJ, Vol. 2, pp. 145–183 (1987).

    Google Scholar 

  4. G. Kazantzis, The mutagenic and carcinogenic effects of cadmium: an update, Toxicol. Environ. Chem. 15, 83–100 (1987).

    Article  CAS  Google Scholar 

  5. F. W. Sunderman, Jr., Mechanism of nickel carcinogenesis, Scand. J. Work Environ. Health 15, 1–12 (1989).

    PubMed  CAS  Google Scholar 

  6. M. İşcan and T. Çoban, Nickel effect on hepatic cytochrome P450 dependent monooxygenases in mice, in Cytochrome P450: Biochemistry and Biophysics, I. Schuster, ed., Taylor & Francis, London, pp. 787–789 (1989).

    Google Scholar 

  7. M. İşcan and A. Karakaya, Cadmium sensitivity differences between liver microsomal drug metabolizing enzyme systems of guinea-pig and rat, Comp. Biochem. Physiol. 90C, 101–105 (1988).

    Google Scholar 

  8. M. İşcan, T. Çoban and B. C. Eke, Responses of hepatic xenobiotic metabolizing enzymes of mouse, rat and guinea pig to nickel, Pharmacol. Toxicol. 71, 434–442 (1992).

    PubMed  Google Scholar 

  9. M. İşcan, T. Çoban and M. İşcan, Combined effect of cadmium and nickel on rat hepatic monooxygenases: possible stimulation of certain cytochrome P-450 isozymes, Toxicol. Lett. 62, 191–199 (1992).

    Article  PubMed  Google Scholar 

  10. M. İşcan, T. Çoban, B. C. Eke, and M. İşcan, The responses of hepatic monooxygenases of guinea pig to cadmium and nickel, Biol. Trace. Element Res. 38, 129–137 (1993).

    Google Scholar 

  11. R. C. Schnell, Cadmium-induced alteration of drug action, Fed. Proc. 37, 28–34 (1978).

    PubMed  CAS  Google Scholar 

  12. M. İşcan, T. Çoban, B. C. Eke, and M. İşcan, Differential responses of hepatic monooxygenases and glutathione S-transferases of mice to a combination of cadmium and nickel, Comp. Biochem. Physiol. 111C, 61–68 (1995).

    Google Scholar 

  13. M. İşcan, T. Çoban, and B. C. Eke, Differential combined effects of cadmium and nickel on hepatic and renal glutathione S-transferases of the guinea pig, Environ. Health. Perspect. 102(Suppl. 9), 69–72 (1994).

    PubMed  Google Scholar 

  14. F. Planas-Bohne and M. Elizade, Activity of glutathione S-transferase in rat liver and kidneys after administration of lead and cadmium, Arch. Toxicol. 66, 365–367 (1992).

    Article  PubMed  CAS  Google Scholar 

  15. C. P. Siegers, M. Schenke, and M. J. Younes, Influence of cadmium chloride, mercuric chloride, and sodium vanadate on the glutathione-conjugating enzyme system in liver, kidney, and brain of mice, Toxicol. Environ. Health 22, 141–148 (1987).

    Article  CAS  Google Scholar 

  16. F. J. Gonzales, C. L. Crespi, and H. V. Gelboin, cDNA-expressed human cytochrome P450s: a new age of molecular toxicology and human risk assessment, Mutat. Res. 247, 113–127 (1991).

    Google Scholar 

  17. M. İşcan, B. C. Eke, and T. Çoban, Combined effects of cadmium and nickel on hepatic glutathione S-transferases in rats, Comp. Biochem. Physiol. 104C, 453–456 (1993).

    Google Scholar 

  18. B. C. Eke and M. İşcan, A study on the combined effects of cadmium and nickel on pulmonary and renal xenobiotic metabolizing enzymes in rats, Toxicol. Lett. 123(Suppl. 1), 51–52, (2001).

    Article  Google Scholar 

  19. M. J. Hoey, The effects of metallic salts on the histology and functioning of the rat testis, J. Reprod. Fertit. 12, 461–471 (1966).

    Article  CAS  Google Scholar 

  20. Ş. Saygı, G. Deniz, O. Kutsal, and N. Vural, Chronic effects of cadmium on kidney, liver, testis and fertility of male rats, Biol. Trace. Element Res. 31, 209–214 (1991).

    Google Scholar 

  21. A. S. Chung and M. D. Maines, Differential effect of cadmium on GSH-peroxidase activity in the Leydig and the Sertoli cells of rat testis. Suppression by selenium and the possible relationship to heme concentration, Biochem. Pharmacol. 36, 1367–1372 (1987).

    Article  PubMed  CAS  Google Scholar 

  22. M. İşcan, E. Arınç, N. Vural, and M. Y. İşcan, In vivo effects of 3-methylcolantrene, phenobarbital, pyrethrum and 2,4,5-T isooctylester on liver lung and kidney microsomal mixed function oxidase system of guinea-pig: a comparative study, Comp. Biochem. Physiol. 77C, 177–190 (1984).

    Google Scholar 

  23. N. Sugawara and C. Sugawara, Selenium protection against testicular lipid peroxidation from cadmium, J. Appl. Biochem. 6, 199–204 (1984).

    PubMed  CAS  Google Scholar 

  24. A. O. Ada, Investigation of the combined effects of cadmium and nickel on rat testicular xenobiotic metabolizing enzymes, M.Sc. thesis, Ankara University, Ankara, Turkey (2000).

    Google Scholar 

  25. M. D. Burke and R. T. Mayer, Ethoxyresorufin; direct fluorometric assay of a microsomal O-dealkylation which is preferentially inducible by 3-methylcholantrene, Drug. Metab. Dispos. 2, 583–588 (1974).

    PubMed  CAS  Google Scholar 

  26. J. Sedlak and R. H. Lindsay, Estimation of total protein-bound and non protein sulphydryl groups in tissue with Ellman’s reagent, Anal. Biochem. 25, 192–205 (1968).

    Article  PubMed  CAS  Google Scholar 

  27. W. H. Habig, M. J. Pabst, and W. B. Jakoby, Glutathione-S-transferase. The first enzymatic step in mercapturic acid formation, J. Biol. Chem. 249, 7130–7139 (1974).

    PubMed  CAS  Google Scholar 

  28. R. Lawrence and R. Burke, Glutathione peroxidase activity in selenium-deficient rat liver, Biochem. Biophys. Res. Commun. 71, 952–958 (1976).

    Article  PubMed  CAS  Google Scholar 

  29. M. Mihara, M. Uchiyama, and K. Fukuzawa, Thiobarbituric acid value on fresh homogenate of rat as a parameter of lipid peroxidation in aging, CCl4 intoxication, and vitamin E deficiency, Biochem. Med. 23, 302–311 (1980).

    Article  PubMed  CAS  Google Scholar 

  30. O. H. Lowry, N. J. Roserbrough, A. L. Farr, and R. J. Randall, Protein measurement with the folin phenol reagent, J. Biol. Chem. 193, 265–275 (1951).

    PubMed  CAS  Google Scholar 

  31. J. Satsmadjis and F. V. Talladouri, Determination of trace metals at concentrations above the linear calibration range by electrothermal atomic absorption spectrometry, Anal. Chimi. Acta 131, 83–90 (1981).

    Article  CAS  Google Scholar 

  32. M. D. Maines and A. Kappas, A regulatio of cytochrome P-450-dependent microsomal drug-metabolizing enzymes by nickel, cobalt, and iron, Clin. Pharmacol. Ther. 22, 780–790 (1977).

    PubMed  CAS  Google Scholar 

  33. M. İşcan and M. D. Maines, Differential regulation of heme and drug metabolism in rat testis and prostate: response to cis-platinum and human chorionic gonadotropin, J. Pharmacol. Exp. Ther. 253, 73–79 (1990).

    PubMed  Google Scholar 

  34. N. Mukhtar, I. P. Lee, G. L. Foureman, and J. R. Bend, Epoxide metabolizing enzyme acivities in rat testes: postnatal development and relative activity in interstitial and spermatogenic cell compartments, Chem. Biol. Interact. 22, 153–165 (1978).

    Article  PubMed  CAS  Google Scholar 

  35. D. W. Nebert, The Ah locus: genetic differences in toxicity, cancer, mutation, and birth defects, Crit. Rev. Toxicol. 20, 153–174 (1989).

    PubMed  CAS  Google Scholar 

  36. D. R. Nelson, L. Koymans, T. Kamataki, J. J. Stegeman, R. Feyereisen, D. J. Waxman, et al., P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature, Pharmacogenetics 6, 1–42 (1996).

    Article  PubMed  CAS  Google Scholar 

  37. D. W. Nebert and F. J. Gonzalez, P450 genes: structure, evolution, and regulation, Annu. Rev. Biochem. 56 945–993 (1987).

    Article  PubMed  CAS  Google Scholar 

  38. T. M. Bray and C. G. Taylor, Tissue glutathione nutrition and oxidative stress, Can. J. Physiol. Pharmacol. 71, 746–751 (1993).

    PubMed  CAS  Google Scholar 

  39. G. Gstraunthaler, W. Pfaller, and P. Kotanko, Glutathione depletion and in vitro lipid peroxidation in mercury or maleate induced acute renal failure, Biochem. Pharmacol. 32, 2969–2972 (1983).

    Article  PubMed  CAS  Google Scholar 

  40. B. Ketterer and G. J. Mulder, Glutathione conjugation, in Conjugation Reactions in Drug Metabolism, G. J. Mulder, ed., Taylor & Francis, London, pp. 307–364 (1990).

    Google Scholar 

  41. B. Mannervik, Y. C. Awasthi, P. G. Board, J. D. Hayes, C. Di Ilio, B. Ketterer, et al., Nomenclature for human glutathione transferases, Biochem. J. 282, 305–308 (1992).

    PubMed  CAS  Google Scholar 

  42. D. J. Meyer, B. Coles, S. E. Pemble, K. S. Gilmore, G. M. Fraser, and B. Ketterer, Theta, a new class of glutathione transferases purified from rat and man, Biochem. J. 274, 409–414 (1991).

    PubMed  CAS  Google Scholar 

  43. E. Campbell, Y. Takahashi, M. Abramovitz, M. Peretz, and I. Listowsky, A distinct human testis and brain μ-class glutathione S-transferase: molecular cloning and characterization of a form present even in individuals lacking hepatic type μ isoenzymes, J. Biol. Chem. 265, 9188–9193 (1990).

    PubMed  CAS  Google Scholar 

  44. J. Gandy, T. Primiano, R. F. Novak, W. R. Kelce, and J. L. York, Differential expression of glutathione S-transferase isoforms in compartments of the testis and segments of the epididymis of the rat, Drug. Metab. Dispos. 24, 725–733 (1996).

    PubMed  CAS  Google Scholar 

  45. B. Mannervik and U. H. Danielson, Glutathione transferases-structure and catalytic activity, Crit. Rev. Biochem. 23, 283–337 (1988).

    CAS  Google Scholar 

  46. B. Ketterer and D. J. Meyer, Glutathione transferases: a possible role in the detoxication and repair of DNA and lipid hydroperoxides, Mutat. Res. 214, 33–40 (1989).

    PubMed  CAS  Google Scholar 

  47. K. H. Tan, D. J. Meyer, J. Belin, and B. Ketterer, Inhibition of microsomal lipid peroxidation by glutathione and glutathione transferases B and AA. Role of endogenous phospholipase A2, Biochem. J. 220, 243–252 (1984).

    PubMed  CAS  Google Scholar 

  48. A. Aoki and A. P. Hoffer, Reexamination of the lesions in rat testis caused by cadmium, Biol. Reprod. 18, 579–591 (1978).

    Article  PubMed  CAS  Google Scholar 

  49. M. D. Maines, Characterization of heme oxygenase activity in Leydig and Sertoli cells of the rat testes. Differential distribution of activity and response to cadmium, Biochem. Pharmacol. 33, 1493–1502 (1984).

    Article  PubMed  CAS  Google Scholar 

  50. M. D. Maines, A. S. Chung, and R. K. Kutty, The inhibition of testicular heme oxygenase activity by cadmium. A novel cellular response, J. Biol. Chem. 257, 14,116–14,121 (1982).

    CAS  Google Scholar 

  51. M. D. Maines, Regional distribution of the enzymes of haem biosynthesis and the inhibition of 5-aminolaevulinate synthase by manganese in the rat brain, Biochem. J. 190, 315–321 (1980).

    PubMed  CAS  Google Scholar 

  52. M. D. Maines and A Kappas, Cobalt stimulation of heme degradation in the liver. Dissociation of microsomal oxidation of heme from cytochrome P-450, J. Biol. Chem. 250, 4171–4177 (1975).

    PubMed  CAS  Google Scholar 

  53. M. D. Maines and J. C. Veltman, Phenylhydrazine-mediated induction of haem oxygenase activity in rat liver and kidney and development of hyperbilirubinaemia. Inhibition by zinc-protoporphyrin, Biochem. J. 217, 409–417 (1984).

    PubMed  CAS  Google Scholar 

  54. S. K. Tandon, S. Kandelwal, A. K. Mathur, and M. Ashquin, Preventive effects of nickel on cadmium hepatotoxicity and nephrotoxicity, Ann. Clin. Lab. Sci. 14, 391–396 (1984).

    Google Scholar 

  55. E. L. B. Novelli, R. T. Hernandez, J. L. V. B. Novelli Filho, and L. L. Barbosa, Differential/combined effect of water contamination with cadmium and nickel on tissues of rats, Environ. Pollut. 103, 295–300 (1998).

    Article  CAS  Google Scholar 

  56. R. W. Chen, P. A. Wagner, W. G. Hoekstra, and H. E. Ganther, Affinity labelling studies with 109 cadmium in cadmium-induced testicular injury in rats, J. Reprod. Fertil. 38, 293–306 (1974).

    Article  PubMed  CAS  Google Scholar 

  57. A. S. Chung and M. D. Maines, Effect of selenium on glutathione metabolism. Induction of gamma-glutamylcysteine synthetase and glutathione reductase in the rat liver, Biochem. Pharmacol. 30, 3217–3223 (1981).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Toxicology, Faculty of Pharmacy, Ankara University, Tandoğan, Ankara, Turkey

    Mümtaz İşcan, Ahmet O. Ada & Tülay Çoban

  2. Department of Pathology, Demetevler Oncology Hospital, Ankara, Turkey

    Nilgün Kapucuoğlu

  3. Department of Pharmaceutical Toxicology, Gülhane Military Medical Academy, Etlik, Ankara, Turkey

    Ahmet Aydin & Aşkin Işimer

Authors
  1. Mümtaz İşcan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ahmet O. Ada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tülay Çoban
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nilgün Kapucuoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahmet Aydin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aşkin Işimer
    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

İşcan, M., Ada, A.O., Çoban, T. et al. Combined effects of cadmium and nickel on testicular xenobiotic metabolizing enzymes in rats. Biol Trace Elem Res 89, 177–190 (2002). https://doi.org/10.1385/BTER:89:2:177

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/BTER:89:2:177

Index Entries

Search

Navigation