Biochemical Mechanisms of Renal Toxicity

Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, Pennsylvania 10104 

Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina 27695 

Nephrotoxicity can be a potentially serious complication of drug therapy or chemical exposure. Although in most instances the mechanisms mediating nephrotoxicity are unclear, susceptibility of the kidney to toxic injury appears to be related, at least in part, to the complexities of renal anatomy and physiology. 

The focus of this chapter is threefold (1) to review components of renal physiology contributing to susceptibility to chemically induced nephrotoxicity, (2) to examine current methodologies for assessment of nephrotoxicity, and (3) to provide examples of a few specific nephrotoxicants, emphasizing mechanisms thought to contribute to the unique or selective susceptibility of specific nephron segments to these toxicants. 

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Tarloff, J. B. Biochemical mechanisms of renal toxicity. In An Introduction to Biochemical Toxicology, 3rd ed., E. Hodgson and R. C. Smart, eds. New York Wiley, 2001, p. 641. Schnellmann R. G, Toxic Responses of the kidney. In Casarett and Doull s Toxicology The Basic Sciences of Poisons, 6th ed., C. D Klaassen, ed, New York McGraw-Hill, 2001, p. 491. 

Beta-lactams such as cephaloridine, cephalothin, ce-fotiam and imipenem have been associated with nephrotoxicity in humans and experimental animals [9]. An understanding of their nephrotoxicity mechanisms may provide valuable information for elucidation of the biochemical mechanisms of newer P-Iactam nephrotoxicity. Similarly to cephaloridine, third- generation cephalosporins such as ceftazidime and cefsulodin and fourth-generation cephalosporins such as cefpirome and cefepime possess a quaternary nitrogen attached to the dihydrothiazine ring which may impart nephrotoxic potential [10]. Clinical and animal studies carried out with P-Iactams, such as cephaloglycin, cephaloridine, cephalothin or imipenem, indicated that they show a differential accumulation at the site of their toxicity, the renal cortex [11]. Elucidation of the mechanism of toxic action of these model (i-lactams has become the focus of several research efforts [12-16]. 

The data indicate that zinc-induced metallothionein binds mercury in the renal cortex and shifts the distribution of mercury from its site of toxicity at the epithelial cells of the proximal tubules. Thus, the renal content of mercury is increased, yet less is available to cause toxicity. In contrast, the renal toxicity of mercuric chloride is exacerbated in zinc-deficient animals (Fukino et al. 1992). In the zinc-deficient state, less mercury accumulates in the kidneys, but the toxicity is greater. The mechanism of the protection appears to involve more than simply a redistribution of renal mercury, because in the absence of mercury exposure, zinc deficiency increases renal oxidative stress (increased lipid peroxidation, decreased reduced ascorbate). When mercury exposure occurs, the oxidative stress is compounded (increased lipid peroxidation and decreased glutathione and glutathione peroxidase). Thus, zinc appears to affect the biochemical protective mechanisms in the kidneys as well. 

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