Abstract
The extensive renal tubular necrosis that results in male rats after the intravenous injection of a single, low dose of equine kidney cadmium (Cd), zinc(Zn)-metallothionein (MT) (0.2 mg MT-bound-Cd/kg body wt.) is followed within 72 h by active regeneration. With repeated administration of the same dose at 3-or 4-day intervals, the lesion resolves although, at least initially, the kidney content of Cd increases progressively. At any time during treatment, about 40% of the accumulated Cd is bound as the endogenous (Cd, Cu)MT. The rate of increase in the renal Cd content is dependent on the ratio of Cd∶Zn in the injected metalloprotein, and is appreciably less when the constant dose of protein-bound Cd is given as a (2.4 Cd∶1 Zn)MT, than as a (3.0 Cd∶1 Zn)MT. On repeated administration of the latter preparation, however, the concentration of Cd in the kidney does not attain a critical concentration, above which persistant tubular damage occurs, but reaches a maximum of about 150–160 μg Cd/g wet wt. (after 16 doses) and then declines. After 19 doses of the (2.4 Cd∶1 Zn)MT under the same conditions, the renal Cd concentration is submaximal and is less (92 μg Cd/g wet wt.) than that after either 16 or 27 doses of the (3.0 Cd∶1 Zn)MT. In animals that are dosed with either of the heterologous MT preparations, the first dose, although not innocuous, seems to protect the kidneys against further damage by subsequent doses. Repeated doses, however, lead to vascular changes, e.g. lymphoid infiltration, periarteriole oedema and dilation of the arcuate veins, and to dilation of the glomerular spaces.
Similar content being viewed by others
References
Banerjee D, Onosaka S, Cherian MG (1982) Immunohistochemical localization of metallothionein in the cell nucleus and cytoplasm of rat liver and kidney. Toxicology 24: 95–105
Bernard A, Goret A, Buchet JP, Roels H, Lauwerys R (1980) Characterization of the proteinuria induced by long term administration of cadmium in rat. Abst 19th Ann Meeting Soc Toxicol, A280
Cain K, Holt DE (1983) Studies of cadmium-thionein induced nephropathy. Time course of cadmium-thionein uptake and degradation. Chem-Biol Interact 43: 223–237
Cain K, Webb M (1983) Metallothionein and its relationship to the toxicity of cadmium and other metals in the young. In Schmidt EHF, Hildenbrandt AG (eds), Health evaluation of heavy metals in infant formula and junior food Springer-Verlag, Berlin, Heidelberg. pp 105–111
Chang CC, Vander Mallie RJ, Garvey SJ (1980) A radioimmunoassay for human metallothionein. Toxicol Appl Pharmacol 55: 94–102
Cherian MG (1978) Induction of renal metallothionein synthesis by parenteral cadmium-thionein in rats. Biochem Pharmacol 27: 1163–1166
Danielson KG, Ohi S, Huang PC (1982) Immunochemical detection of metallothionein in specific epithelial cells of rat organs. Proc Natl Acad Sci USA 79: 2301–2304
Foulkes EC (1978) Renal tubular transport of cadmium metallothionein. Toxicol Appl Pharmacol 34: 473–487
Frazier JM (1982) The role of metallothionein in the systemic distribution of cadmium. In Foulkes EC (ed), Biological roles of metallothionein Elsevier/North Holland, New York, Amsterdam, Oxford pp 141–153
Johnson DR, Foulkes EC (1980) On the proposed role of metallothionein in the transport of cadmium. Environ Res 21: 350–356
Kägi JHR, Himmelhoch SR, Whanger PD, Bethune JL, Vallee BL (1974) Equine hepatic and renal metallothioneins. Purification, molecular weight, amino acid composition and metal content. J Biol Chem 249: 3537–3542
Kotsonis FN, Klaassen CD (1981) Metallothionein and its interaction with cadmium. In Nriagu JO (ed) Cadmium in the environment, II Health Effects Wiley, New York, Chichester, Brisbane, Toronto, Singapore pp 595–616
Lauwerys BR, Roels AA, Buchet J-P, Bernard A, Stanescu D (1979) Investigation of the lung and kidney function in workers exposed to cadmium. Environ Health Perspect 28: 137–145
Margoshes M, Vallee BL (1957) A cadmium protein from equine kidney cortex. J Am Chem Soc 79: 4813–4814
Mehra RK, Bremner I (1983) Development of a radioimmunoassay for rat liver metallothionein-1 and its application to the analysis of rat plasma and kidneys. Biochem J 213: 459–465
Murakami M, Cain K, Webb M (1983) Cadmium-metallothionein-induced nephropathy: A morphological and autoradiographical study of cadmium distribution, the development of tubular damage and subsequent cell regeneration. J Appl Toxicol 3: 237–244
Murakami M, Webb M (1981) A morphological and biochemical study of the effects of L-cysteine on the renal uptake and nephrotoxicity of cadmium. Br J Exp Pathol 62: 115–130
Nomiyama K, Foulkes EC (1977) Reabsorption of filtered cadmiummetallothionein in the rabbit kidney. Proc Soc Exp Biol Med 156: 97–99
Nomiyama K, Nomiyama H (1982) Tissue metallothioneins in rabbits chronically exposed to cadmium, with special reference to the critical concentration of cadmium in the renal cortex. In Foulkes EC (ed), Biological roles of metallothionein, Elsevier/North Holland, New York, Amsterdam, Oxford pp 46–67
Ridlington JW, Winge DR, Fowler BA (1981) Long term turnover of cadmium-metallothionein in liver and kidneys following a single low dose of cadmium. Biochim Biophys Acta 673: 177–183
Selenke W, Foulkes EC (1981) Binding of cadmium metallothionein to isolated renal brush border membranes. Proc Soc Exp Biol Med 167: 40–44
Sokolowski G, Weser U (1975) Formation, circular dichroism and X-ray photoelectron spectroscopy of hepatic Zn-thionein. Hoppe-Seyler's Z Physiol Chem 356: 1715–1726
Squibb KS, Pritchard JB, Fowler BA (1982) Renal metabolism and toxicity of metallothionein. In Foulkes EC (ed), Biological roles of metallothionein, Elsevier/North Holland, New York, Amsterdam, Oxford pp 181–192
Suzuki KT (1982) Induction and degradation of metallothionein and their relation to the toxicity of cadmium. In Foulkes EC (ed), Biological roles of metallothionein, Elsevier/North Holland, New York, Amsterdam, Oxford pp 215–235
Suzuki KT, Takenaka S, Kubota K (1979) Fate and comparative toxicity of metallothioneins with different Cd ∶ Zn ratios in rat kidney. Arch Environ Contain Toxicol 8: 85–95
Tohyama C, Shaikh ZA (1978) Cross reactivity of metallothioneins from different origins with rabbit and rat hepatic metallothionein antibody. Biochem Biophys Res Commun 84: 907–913
Tohyama C, Shaikh ZA (1981) Metallothionein in plasma and urine of cadmium exposed rats determined by a single antibody radioimmunoassay. Fund Appl Toxicol 1: 1–17
Tohyama C, Shaikh ZA, Nogawa K, Kobayashi E, Honda R (1982) Urinary metallothionein as a new index of renal dysfunction in itai itai disease patients and other Japanese women environmentally exposed to cadmium. Arch Toxicol 50: 159–166
Vallee BL (1979) Metallothionein: Historical review and perspectives. In Kägi JHR and Nordberg M (eds), Metallothionein, Birkhauser, Verlag, Basel, Boston, Stuttgart pp 19–24
Vander Mallie RJ, Garvey JS (1979) Radioimmunoassay of metallothioneins. J Biol Chem 254: 8416–8421
Webb M (1979a) The metallothioneins. In Webb M (ed), The chemistry, biochemistry and biology of cadmium Elsevier/North Holland, Amsterdam, New York, Oxford pp 195–266
Webb M (1979b) Cadmium-thionein and the nephrotoxicity of cadmium. In Anke M, Schneider HJ (eds), Friedrich-Schiller Universität Jena (Kadmium Symposium 101–107)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Holt, D., Sparrow, S. & Webb, M. The chronic toxicity of equine cadmium metallothionein in the rat. Arch Toxicol 57, 200–204 (1985). https://doi.org/10.1007/BF00290888
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00290888