Toxicology- From Cells to Man

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Renal transport and xenobiotic metabolism play an important role in the detoxication and excretion of potentially toxic xenobiotics. However, recent experimental evidence has demonstrated that renal xenobiotic metabolism and renal transport processes also play an important role in the nephrotoxicity of xenobiotics and xenobiotic metabolites. The high blood flow to the kidney combined with its ability to concentrate solutes may expose the kidney to high concentrations of xenobiotics and xenobiotics metabolites present in the systemic circulation. Recently, it has been demonstrated that xenobiotic metabolites formed in the liver and other organs may be targeted to the kidney by selective transport systems~ many xenobiotics require enzymatic transformation to proximate reactive metabolites to elicit their toxic and carcinogenic effects. The enzymatic formation of reactive metabolites is termed bioactivation. The bioactivation mechanisms for many nephrotoxicants have, at least in part, been elucidated in the past 15 years. Many ultimate toxicants formed in the kidney are electrophiles whose interaction with cellular macromolecules may cause a perturbation of normal cell function resulting in necrosis and/or cancer (Anders 1988). Electrophilic metabolites may bind to nucleophilic sites in cellular macromolecules~ the importance of covalent modification of protein and DNA in cell killing and in the induction of tumors is established (Miller and Miller 1981~ Nelson and Pearson 1990~ Hinson and Roberts 1992). The objective of this review is to summarize new information about renal transport, renal bioactivation and their relation to nephrotoxicity using two relevant example for the basic mechanisms outlined above.