Date of Award
1989
Degree Type
Dissertation
Degree Name
Doctor of Philosophy
Abstract
The critical organ of toxicity after chronic cadmium (Cd) exposure is the kidney. This toxicity can be modified by intracellular interactions of Cd with metallothionein (MT) or glutathione (GSH). Since the Cd-bound form of MT (Cd-MT) is a potent nephrotoxic agent, Cd-MT was used as a model for investigations of Cd-induced renal disease.;After Cd-MT injection in rats, urinary enzymes were used as subcellular markers of renal damage. The maximal excretion of two brush border membrane (BBM) enzymes preceded the maximal excretion of a lysosomal enzyme indicating early damage to the BBM with subsequent lysosomal damage. Pretreatment with zinc (Zn) increased intracellular MT concentrations and appeared to protect against the Cd-MT-induced lysosomal damage but not the brush border effects.;In both in vivo and in vitro studies, Cd-MT was much more nephrotoxic than CdCl{dollar}\sb2{dollar}. After Cd-MT injection, the renal accumulation of Cd was more rapid with a smaller proportion of Cd being bound to MT as compared to the Cd of CdCl{dollar}\sb2{dollar}. In vitro, although Cd-MT had a slightly greater inhibitory effect on anionic transport than equimolar Cd concentrations of CdCl{dollar}\sb2{dollar}, the accumulation of Cd in the slices was approximately 12 times greater with CdCl{dollar}\sb2{dollar}. Therefore the greater renal toxicity of Cd-MT as compared to CdCl{dollar}\sb2{dollar} appears to be related not only to the renal accumulation of the Cd ion but may also be due in part to differences in uptake mechanisms and the intracellular partitioning and binding of the metal.;Reduction of tissue GSH concentrations markedly increased the renal toxicity of Cd-MT. This toxicity was only slightly attenuated by increased renal MT concentrations. These results suggest that both GSH and MT can influence the renal toxicity of Cd-MT.;The effect of MT and GSH on the renal toxicity of cisdiamminedichloroplatinum (c-DDP) in rats was also investigated. The Pt moiety of c-DDP did not induce the synthesis of, or bind to, MT. An increase in intracellular Zn-MT or the depletion of GSH concentrations prior to c-DDP injection did not greatly alter the toxicity of c-DDP to the kidney suggesting that neither MT nor GSH may play any major role in the onset of cDDP-induced nephrotoxicity.
Recommended Citation
Suzuki, Catherine Ann, "Studies On The Factors Affecting The Renal Toxicity Of Cadmium Metallothionein And Cis-diamminedichloroplatinum" (1989). Digitized Theses. 1803.
https://ir.lib.uwo.ca/digitizedtheses/1803