Mechanism of the Mitochondrial Respiratory Toxicity of Cephalosporin Antibiotics

  • Bruce M. Tune
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 252)

Abstract

The beta-lactam antibiotics exert their antimicrobial action by acylating and inactivating several functionally important bacterial membrane-bound proteins (Waxman and Strominger, 1983). This action is highly specific, and the beta-lactams have, in general, very favorable toxic- therapeutic ratios. However, several cephalosporins (Tune, 1986), and the new thienamycin antibiotic imipenem (Bimbaum et al., 1985), can cause acute renal failure when given under high-risk conditions. This toxicity is seen as an acute proximal tubular necrosis (Silverblatt et al., 1970), occurs in proportion to the concentrative uptake of the antibiotics by the tubular cell (Tune, 1975), and is prevented by inhibitors of this secretory transport (Tune and Fravert, 1980a).

Keywords

Toxicity Ischemia Manifold Respiration Lime 

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References

  1. Bendirdjian, J.-P., Prime, D.J., Browning, M.C., and Tune, B.M.: The mitochondrial respiratory toxicity of cephalosporins - Molecular properties and pathogenic significance. In: Nephrotoxicity, ototoxicity of drugs. J.-P. Fillastre (Ed.), Editions INSERM, Universite de Rouen, France, 1982, pp. 303–319.Google Scholar
  2. Birnbaum, J., Kahan, F.M., Kropp, H., and MacDonald, J.S.: Carbapenems. A new class of beta-lactam antibiotics. Discovery and improvement of ImipenenVCilastatin. Amer. J. Med., 78 (suppl 6A): 3–21,1985.PubMedCrossRefGoogle Scholar
  3. Browning, M.C., and Tune, B.M.: Reactivity and binding of beta-lactam antibiotics in rabbit renal cortex. J. Pharmacol. Exper. Therap., 226:640–644, 1983.Google Scholar
  4. Hanstein, W.G.: Uncoupling of oxidative phosphorylation. Biochim. Biophys. Acta, 456:129–148, 1976.PubMedCrossRefGoogle Scholar
  5. Holtzman, D., and Moore, C.L.: Respiration in immature rat brain mitochondria. J. Neurochem., 24:1011–1015, 1975.PubMedCrossRefGoogle Scholar
  6. Indelicato, J.M., Dinner, A., Peters, L.R., and Wilham, W.L.: Hydrolysis of 3-chloro-3-cephems. Intramolecular nucleophilic attack in cefaclor. J. Med, Chem., 20:961–963, 1977.CrossRefGoogle Scholar
  7. Palmieri, F., and Klingenberg, M.: Direct methods for measuring metabolite transport and distribution in mitochondria. Meth. Enzymol, 56:279–301, 1979.PubMedCrossRefGoogle Scholar
  8. Silverblatt, F., Turck, M., and Bulger, R.: Nephrotoxicity due to cephaloridine: A light- and electron-microscopic study in rabbits, J. Infect. Dis., 122:33–44, 1970.PubMedCrossRefGoogle Scholar
  9. Slater, E.G.: Application of inhibitors and uncouplers for a study of oxidative phosphorylation. Meth. EnzymoL, 10:48–57, 1967.CrossRefGoogle Scholar
  10. Tune, B.M.: The nephrotoxicity of cephalosporin antibiotics - Structure-activity relationships. Comments on Toxicology, 1:145–170, 1986.Google Scholar
  11. Tune, B.M.: Relationship between the transport and toxicity of cephalosporins in the kidney. J. Infect. Dis., 132:189–194, 1975.PubMedCrossRefGoogle Scholar
  12. Tune, B.M., and Fravert, D.: Mechanisms of cephalosporin nephrotoxicity. A comparison of cephaloridine and cephaloglycin. Kidney Int., 18:591–600,1980a.PubMedCrossRefGoogle Scholar
  13. Tune, B.M., and Fravert, D.: Cephalosporin nephrotoxicity. Transport, cytotoxicity and mitochondrial toxicity of cephaloglycin. J. Pharmacol. Exper. Therap., 215:186–190, 1980b.Google Scholar
  14. Tune, B.M., Sibley, R.K., and Hsu, C.-Y.: The mitochondrial respiratory toxicity of cephalosiprin antibiotics. An inhibitory effect on substrate uptake. J. Pharmacol. Exper. Therap., in press.Google Scholar
  15. Tune, B.M., Wu, K.-Y., Fravert, D., and Holtzman, D.: Effect of cephaloridine on respiration by renal cortical mitochondria. J. Pharmacol, Exper. Therap., 210:98–100, 1979.Google Scholar
  16. Venkatachalam, M.A., Bernard, D.B., Donohoe, J.F., and Levinsky, N.G.: Ischemic damage and repair in the rat proximal tubule: Differences among the Si, Si, and S3 segments. Kidney Int., 14:31–49, 1978.PubMedCrossRefGoogle Scholar
  17. Waxman, D.J., and Strominger, J.L.: Penicillin binding proteins and the mechanism of action of beta-lactam antibiotics. Ann. Rev. Biochem., 52:825–869, 1983.PubMedCrossRefGoogle Scholar
  18. Yamana, T., and Tsuji, A.: Comparative stability of cephalosporins in aqueous solution: Kinetics and mechanisms of degradation. J. Pharmaceut. Sci., 65:1563–1574, 1976.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Bruce M. Tune
    • 1
  1. 1.Department of PediatricsStanford UniversityStanfordUSA

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