Cellular and Molecular Mechanisms of Toxicity

To enter the intracellular space, Cd in extracellular fluids that is present as a free ion or complexed to proteins or peptides must permeate lipophilic cellular membranes. This occurs through intrinsic proteinous pathways. Free Cd may be transported via ion channels and solute carriers and Cd complexes may be taken up through receptor-mediated endocytosis. Cd has similar chemical properties as essential metals ( ionic mimicry ) and Cd complexes are analogous to endogenous biological molecules ( molecular mimicry ) [447,448]. Hence, transport (and toxicity) of Cd can only occur if cells possess transport pathways for essential 

A variety of pathways have been suggested to allow Cd entry in excitable and non-excitable cells [193]. The most likely candidates, whose molecular structures have been identified, are listed in Table 1. Proof of their Cd transporting abilities has been obtained using stringent experimental approaches, such as radiotracer, fluorescent dye and/or electrophysiological transport assays combined with molecular biology techniques. Further information is available in a recent detailed review [199]. 

2 Interference with Transport and Homeostasis of Essential Metals and Biological Molecules 

most of the studies describing direct effects of Cd on the function of transporters (reviewed in [277]) may have only in vitro or mechanistic relevance and are not likely to significantly contribute to in vivo toxicity of Cd in tissues. Indeed, few mammalian transporters are directly affected by submicromolar Cd concentrations Ca-ATPase of rat intestinal and renal basolateral plasma membrane is blocked with an IC50 of 1.6 nM [464] and apical Na-dependent glucose and amino transporters of isolated rabbit PT (S2-segment) by nanomolar concentrations of CdMT [221]. However, it cannot be excluded that the effects observed were due to CdMT-induced endocytosis of apical membranes containing Na-dependent 

Name Endogenous substrates Localization Transport mechanism Function Cd affinity (K /Kd/EC5o) References 

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Richburg JH, Johnson KJ, Schoenfeld HA et al. Defining the cellular and molecular mechanisms of toxicant action in the testis. Toxicol Lett 2002 135 167-183. 

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