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. 1990 Mar;84:107–111. doi: 10.1289/ehp.9084107

The role of calcium ions in toxic cell injury.

J L Farber 1
PMCID: PMC1567653  PMID: 2190804

Abstract

Calcium ions have been increasingly implicated as a mediator of the mechanisms generating lethal cell injury under a variety of pathologic circumstances. An overview of the various roles suggested for such alterations in cellular calcium homeostasis is presented. The central role of plasma membrane damage in the genesis of irreversible cell injury is used to divide the postulated roles for calcium ions into two major mechanisms. On the one hand, calcium ions have been proposed as mediators of the functional consequences of plasma membrane injury. An influx of extracellular calcium ions across a damaged permeability barrier and down a steep concentration gradient may convert potentially reversible injury into irreversible injury. On the other hand, alterations in intracellular calcium homeostasis are postulated to participate in the mechanisms generating potentially lethal plasma membrane injury. The release of calcium stores sequestered within intracellular organelles raises the cytosolic concentration of free calcium, a process that may activate, in turn, a number of membrane-disruptive processes. The data supporting these two distinct actions of calcium are reviewed and discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bellomo G., Jewell S. A., Thor H., Orrenius S. Regulation of intracellular calcium compartmentation: studies with isolated hepatocytes and t-butyl hydroperoxide. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6842–6846. doi: 10.1073/pnas.79.22.6842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bellomo G., Orrenius S. Altered thiol and calcium homeostasis in oxidative hepatocellular injury. Hepatology. 1985 Sep-Oct;5(5):876–882. doi: 10.1002/hep.1840050529. [DOI] [PubMed] [Google Scholar]
  3. Bellomo G., Thor H., Orrenius S. Increase in cytosolic Ca2+ concentration during t-butyl hydroperoxide metabolism by isolated hepatocytes involves NADPH oxidation and mobilization of intracellular Ca2+ stores. FEBS Lett. 1984 Mar 12;168(1):38–42. doi: 10.1016/0014-5793(84)80202-1. [DOI] [PubMed] [Google Scholar]
  4. Chien K. R., Abrams J., Pfau R. G., Farber J. L. Prevention by chlorpromazine of ischemic liver cell death. Am J Pathol. 1977 Sep;88(3):539–557. [PMC free article] [PubMed] [Google Scholar]
  5. Di Monte D., Bellomo G., Thor H., Nicotera P., Orrenius S. Menadione-induced cytotoxicity is associated with protein thiol oxidation and alteration in intracellular Ca2+ homeostasis. Arch Biochem Biophys. 1984 Dec;235(2):343–350. doi: 10.1016/0003-9861(84)90207-8. [DOI] [PubMed] [Google Scholar]
  6. Di Monte D., Ross D., Bellomo G., Eklöw L., Orrenius S. Alterations in intracellular thiol homeostasis during the metabolism of menadione by isolated rat hepatocytes. Arch Biochem Biophys. 1984 Dec;235(2):334–342. doi: 10.1016/0003-9861(84)90206-6. [DOI] [PubMed] [Google Scholar]
  7. El-Mofty S. K., Scrutton M. C., Serroni A., Nicolini C., Farber J. L. Early, reversible plasma membrane injury in galactosamine-induced liver cell death. Am J Pathol. 1975 Jun;79(3):579–596. [PMC free article] [PubMed] [Google Scholar]
  8. Gárdos G., Lassen U. V., Pape L. Effect of antihistamines and chlorpromazine on the calcium-induced hyperpolarization of the Amphiuma red cell membrane. Biochim Biophys Acta. 1976 Nov 2;448(4):599–606. doi: 10.1016/0005-2736(76)90113-9. [DOI] [PubMed] [Google Scholar]
  9. Jaanus S. D., Miele E., Rubin R. P. The action of guanethidine on the adrenal medulla of the cat. Br J Pharmacol Chemother. 1968 Jul;33(3):560–569. doi: 10.1111/j.1476-5381.1968.tb00505.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Masaki N., Kyle M. E., Farber J. L. tert-butyl hydroperoxide kills cultured hepatocytes by peroxidizing membrane lipids. Arch Biochem Biophys. 1989 Mar;269(2):390–399. doi: 10.1016/0003-9861(89)90122-7. [DOI] [PubMed] [Google Scholar]
  11. Moore G. A., Jewell S. A., Bellomo G., Orrenius S. On the relationship between Ca2+ efflux and membrane damage during t-butylhydroperoxide metabolism by liver mitochondria. FEBS Lett. 1983 Mar 21;153(2):289–292. doi: 10.1016/0014-5793(83)80626-7. [DOI] [PubMed] [Google Scholar]
  12. Nicotera P., Hartzell P., Baldi C., Svensson S. A., Bellomo G., Orrenius S. Cystamine induces toxicity in hepatocytes through the elevation of cytosolic Ca2+ and the stimulation of a nonlysosomal proteolytic system. J Biol Chem. 1986 Nov 5;261(31):14628–14635. [PubMed] [Google Scholar]
  13. Olafsdottir K., Pascoe G. A., Reed D. J. Mitochondrial glutathione status during Ca2+ ionophore-induced injury to isolated hepatocytes. Arch Biochem Biophys. 1988 May 15;263(1):226–235. doi: 10.1016/0003-9861(88)90631-5. [DOI] [PubMed] [Google Scholar]
  14. Rush G. F., Yodis L. A., Alberts D. Protection of rat hepatocytes from tert-butyl hydroperoxide-induced injury by catechol. Toxicol Appl Pharmacol. 1986 Jul;84(3):607–616. doi: 10.1016/0041-008x(86)90267-x. [DOI] [PubMed] [Google Scholar]
  15. Schanne F. A., Pfau R. G., Farber J. L. Galactosamine-induced cell death in primary cultures of rat hepatocytes. Am J Pathol. 1980 Jul;100(1):25–38. [PMC free article] [PubMed] [Google Scholar]
  16. Schreiner G. F., Unanue E. R. The disruption of immunoglobulin caps by local anesthetics. Clin Immunol Immunopathol. 1976 Sep;6(2):264–269. doi: 10.1016/0090-1229(76)90118-5. [DOI] [PubMed] [Google Scholar]
  17. Seeman P., Chen S. S., Chau-Wong M., Staiman A. Calcium reversal of nerve blockade by alcohols, anesthetics, tranquilizers, and barbiturates. Can J Physiol Pharmacol. 1974 Jun;52(3):526–534. doi: 10.1139/y74-070. [DOI] [PubMed] [Google Scholar]
  18. Seeman P. The membrane actions of anesthetics and tranquilizers. Pharmacol Rev. 1972 Dec;24(4):583–655. [PubMed] [Google Scholar]
  19. Starke P. E., Farber J. L. Endogenous defenses against the cytotoxicity of hydrogen peroxide in cultured rat hepatocytes. J Biol Chem. 1985 Jan 10;260(1):86–92. [PubMed] [Google Scholar]
  20. Starke P. E., Farber J. L. Ferric iron and superoxide ions are required for the killing of cultured hepatocytes by hydrogen peroxide. Evidence for the participation of hydroxyl radicals formed by an iron-catalyzed Haber-Weiss reaction. J Biol Chem. 1985 Aug 25;260(18):10099–10104. [PubMed] [Google Scholar]
  21. Starke P. E., Hoek J. B., Farber J. L. Calcium-dependent and calcium-independent mechanisms of irreversible cell injury in cultured hepatocytes. J Biol Chem. 1986 Mar 5;261(7):3006–3012. [PubMed] [Google Scholar]
  22. Thor H., Hartzell P., Orrenius S. Potentiation of oxidative cell injury in hepatocytes which have accumulated Ca2+. J Biol Chem. 1984 May 25;259(10):6612–6615. [PubMed] [Google Scholar]
  23. Williams J. A., Poulsen J. H., Lee M. Effects of membrane stabilizers on pancreatic amylase release. J Membr Biol. 1977 May 6;33(1-2):185–195. doi: 10.1007/BF01869515. [DOI] [PubMed] [Google Scholar]

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