Mercury nephrotoxicity

It has been suggested that mitochondrial injury was a late and possibly secondary event in mercury nephrotoxicity in rats [224], However, compromised mitochondrial bioenergetic function was later proposed to be one of the earliest intracellular effects of mercuric chloride in the production of nephrotoxicity [226, 227],... 

Nicholson JK, Kendall MD,and Osborn D. Cadmium and mercury nephrotoxicity. Nature 304 633-635,1983. 

Zalups, RK Mercer University Macon Macon, GA Mercury nephrotoxicity after a reduction of renal mass. NIEHS... 

Nicholson, J.K. Timbrell, J.A. Sadler, P.J. Proton NMR Spectra of Urine as Indicators of Renal Damage Mercury Nephrotoxicity in Rats. Mol. Pharmacol. 27, 644-651 (1985). 

Thimerosal is a preservative used in vaccines that has been purported to cause autism in children. The assumption is that thimerosal, also known as ethyl mercury, causes similar effects as methyl mercury, which has neurotoxic and nephrotoxic... 

In addition to intensive supportive care, prompt chelation with oral or intravenous unithiol, intramuscular dimercaprol, or oral succimer may be of value in diminishing nephrotoxicity after acute exposure to inorganic mercury salts. Vigorous hydration may help to maintain urine output, but if acute renal failure ensues, days to weeks of hemodialysis or hemodiafiltration in conjunction with chelation may be necessary. Because the efficacy of chelation declines with time since exposure, treatment should not be delayed until the onset of oliguria or other major systemic effects. 

These proteins are important for binding potentially toxic metals such as cadmium, mercury, and lead, which all bind to sulfydryl groups. Consequently, the binding and removal of these metals are protective functions. Metallothioneins are markedly induced by cadmium exposure and the small protein, rich in SH groups, can then sequester the metal. They also may have a protective role in oxidative stress and protect redox-sensitive processes. The protein also has a role in cadmium nephrotoxicity (see chap. 7). 

Mercury. Mercury exerts its principle nephrotoxic effect on the membrane of the proximal tubule cell. In low concentrations, mercury binds to the sulfhydryl groups of membrane proteins and acts as a diuretic by inhibiting sodium reabsorption. Organomer-curial diuretics were introduced into clinical practice in the 1920s and were used... 

Despite several warnings over many years, the use of mercuric chloride solutions during operations in an attempt to kill cancer cells implanted in healthy tissues persists in some countries. Intraperitoneal administration, when seeding of a visceral cancer is feared, carries the risk of mercury absorption and nephrotoxicity. Death from intoxication after peritoneal lavage with a mercuric chloride solution has been reported (3). 

The mechanisms of cisplatin-induced nephrotoxicity have not been fully elucidated. Like several nephrotoxic heavy metals (for example mercury), cisplatin can accumulate in the kidney, where it can interact with sulfhydryl compounds, resulting in increased membrane fragility and depletion of intracellular glutathione. There is some evidence that cisplatin can induce apoptosis and necrosis of kidney cells dose-dependently. In vitro studies have suggested that the constitutive expression of antiapoptotic proteins (for example bcl-X) might be inversely correlated with the sensitivity of renal tubular cells (146,195-197). 

The nephrotoxicity of dsplatin is reduced in humans [132], mice [133] and dogs [134] by co-admin-istration of probenecid, suggesting that cisplatin is transported by the PAH transport system. It has been proposed that platinum, hke other nephrotoxic metal ions such as mercury and potassium dichromate, are taken up by tubular cells as sulphydryl conjugate through a probenecid-sensitive pathway [133]. However, cisplatin might also be transported by the organic cation transport system, since quinidine, cimetidine and ranitidine inhibited its net secretion flux in the dog kidney [134]. 

Finally, the nephrotoxicity of inorganic mercury (i.e. mercuric chloride) has been shown to be the result of a GSH or cysteine conjugate. In a series of experiments, Zalups has shown that mercuric chloride in the blood is conjugated to cysteine and GSH as mono- or di-substituted conjugates and to serum proteins [38]. 

Roels HA, Hoet P, Lison D. Usefulness of biomarkers of exposure to inorganic mercury, lead, or cadmium in controlling occupational and environmental risks of nephrotoxicity. Ren Fail. 1999 May-Jul 21(3-4) 251-62. 

The nephrotoxic potential of mercury is related to its accumulation in the proximal tubule region and the intracellular binding to several functional groups, especially thiols, which results in inactivation of different enzymes and inhibition of protein synthesis... 

Woods JS, Dieguez-Acuna EJ, Ellis ME, Kushleika J, and Simmonds PE. Attenuation of nuclear factor kappa B (NF-kappaB) promotes apoptosis of kidney epithelial cells a potential mechanism of mercury-induced nephrotoxicity. Environ Eiealth Perspect 110 SuppI 5 819-822, 2002. 

Although there is experimental evidence of nephrotoxicity from methyl mercury in animals, no reports of human renal toxicity from methyl mercury exposure have been identified [14]. 

Organic mercurials are capable of inducing nephrotoxicity in S2 and S3 segments of the proximal tubule. Part of the S3 damage results from the biotransformation of the organic mercurial to release mercuric ions. Methylmercury (CH3Hg + ) readily concentrates in renal proximal tubular cells and alters mitochondrial function and lysosomes. At least part of methylmercury-induced nephrotoxicity may be due to homolytic scission of methylmercury to release methyl radicals and to lipid peroxidative toxicity. 

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