Nephrotoxicants

Mercuric chloride is a potent nephrotoxicant in the adult rat, but has little effect on the newborn [222], There are significant maturational changes in organ, cellular and subcellular distribution of mercury during the first 4 weeks after birth. With increasing age, mercury is redistributed from the renal cytosolic fraction to the nuclear/mitochondrial fraction, where it may be more damaging. 

Terlouw SA, Masereeuw R, Russel FG, Miller DS (2001) Nephrotoxicants induce endothelin release and signaling in renal proximal tubules Effect on drug efflux. Mol Pharmacol 59 1433-1440... 

R. J. Griffin, P. J. Harvison, In vivo Metabolism and Disposion of the Nephrotoxicant /V-(3.5-1)ic111(11(ip11enyI)succinimide in Fischer 344 Rats , Drug Metab. Dispos. 1998,... 

The toxicity of mixtures of chemicals with the same target organ was examined in rats using nephrotoxicants with similar or dissimilar modes of action. 

In a subsequent study, the additivity assumption (dose addition) was tested, using the similarly acting nephrotoxicants tetrachloroethylene, trichloroethylene, hexachloro-1,3-butadiene (HCBD), and l,l,2-trichloro-3,3,3-trifluoropropene (Jonker et al. 1996). The compounds were given to female rats by daily oral gavage for 32 days either alone, at the LONEL and NONEL (= LONEL/4), or in combinations of four (at the NONEL and LONEL/2) or three (at the LONEL/3) (see Table 10.9). 

Four-Week Oral Toxicity Study in Female Rats with Mixtures of Nephrotoxicants Having Similar Modes of Action... 

Jonker, D., R.A. Woutersen, P.J. van Bladeren, H.P. Til, and V.J. Feron. 1993. Subacute (4-wk) oral toxicity of a combination of four nephrotoxicants in rats Comparison with the toxicity of the individual compounds. 

Kramer JA, Pettit SD, Amin RP et al. Overview on the application of transcription profiling using selected nephrotoxicants for toxicology assessment. Environ Health Perspect 2004 112 460-464. Newton RK, Aardema M, Aubrecht J. The utility of DNA microarrays for characterizing genotoxicity. Environ Health Perspect 2004 112 420 22. 

Nervous System. The nervous system is also a common target of toxic metals particularly, organic metal compounds (see Chapter 16). For example, methylmercury, because it is lipid soluble, readily crosses the blood-brain barrier and enters the nervous system. By contrast, inorganic mercury compounds, which are more water soluble, are less likely to enter the nervous system and are primarily nephrotoxicants. Likewise organic lead compounds are mainly neurotoxicants, whereas the first site of inorganic lead is enzyme inhibition (e.g., enzymes involved in heme synthesis). 

Inorganic mercury salts, however, are primarily nephrotoxicants, with the site of action being the proximal tubular cells. Mercury binds to SH groups of membrane proteins, affecting the integrity of the membrane and resulting in aliguria, anuria, and uremia. 

Chloroform is a common industrial organic solvent that can be a hepatotoxicant or a nephrotoxicant in both humans and animals. As a nephrotoxicant it is both species and gender dependent. For example, following chloroform administration male mice develop primarily kidney necrosis whereas female develop liver necrosis. 

IchimuraT, Hung CC, Yang SA, et al. Kidney injury molecule-1 a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am JRenal Physiol 2004 286(3) F552-63. 

Jonker et al. (1996) administered female rats with a mixture of 4 nephrotoxicants tet-rachloroethylene, trichloroethylene, hexachloro-1,3-butadiene, and 1,1,2-trichloro-... 

Jonker D, Woutersen RA, Feron VJ. 1996. Toxicity of mixtures of nephrotoxicants with similar or dissimilar mode of action. Food Chem Toxicol 34 1075-1082. 

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. 

Several laboratories have developed methods to physically separate and characterize the metabolic capacity of glomeruli, proximal tubules, and distal tubules. These techniques can offer insight into biochemical changes associated with site-specific nephrotoxicity. Additionally, micropuncture and microperfusion experiments have been utilized to help identify specific loci of action of nephrotoxicants. 

Finally, histopathologic examination of tissue can reveal structural changes that have occurred in response to nephrotoxicants, often allowing identification of affected areas of the nephron (Figure 29.8). For instance, fight microscopy can identify changes in renal morphology caused by chemicals, such as the presence of... 

Fortunately, the kidney has a remarkable ability to compensate for the loss of renal functional mass. Within a short time after unilateral nephrectomy, the remaining kidney hypertrophies such that overall renal function appears normal by standard clinical tests. Compensation becomes a problem when evaluating the effects of nephrotoxicants specifically, changes in kidney function may not be detected until the ability of the kidney to compensate is exceeded. Then, within a short period of time, an animal might develop life-threatening renal failure. 

Chloroform is a nephrotoxicant that most likely undergoes metabolic bioactivation within the kidney. Chloroform (CHC13), a common organic solvent widely used in the chemical industry, produces hepatic and renal injury in humans and experimental animals. Renal necrosis due to chloroform is sex- and species-specific For example, male mice exhibit primarily renal necrosis whereas female mice develop... 

It is well known that a large number of chemical substances, including toxic metals and metalloids such as arsenic, cadmium, lead, and mercury, cause cell injury in the kidney. With metal-induced neurotoxicity, factors such as metal-binding proteins, inclusion bodies, and cell-specific receptor-like proteins seem to influence renal injury in animals and humans. It is of interest to note that certain renal cell populations become the targets for metal toxicity, while others do not. In fact, the target cell populations handle the organic and common inorganic nephrotoxicants differently. ... 

No information was located regarding the modulation of the toxicity of uranium by other chemicals or vice versa. It is possible that co-exposure to other heavy metal nephrotoxicants (e.g., lead, cadmium) could have an additive effect on uranium toxicity. 

Animal studies designed to examine the combined effects on the kidney of uranium and other heavy metal nephrotoxicants Gead, cadmium) would also be useful to determine whether effects are less than expected on the basis of individual toxicity, additive or synergistic. It is possible at some waste sites that multiple exposures to these metals could occur in humans. 

Oncosis/ necrosis is characterized by organelle and cell swelling, cell rupture, and release of intracellular contents, which initiates an inflammatory response that is not observed in apoptosis. It is common for some toxicants to cause apoptosis at low concentrations and oncosis at high concentrations. Because apoptosis is an ATP-dependent process, nephrotoxicants that target the mitochondria and/or induce a decreased ATP predominantly cause oncosis rather than apoptosis [51, 52]. If cellular ATP levels are low and the mitochondrial membrane potential is quickly lost, then oncosis... 

Counts RS, Nowak G, Wyatt RD, and Schnellmann RG. Nephrotoxicant inhibition of renal proximal tubule cell regeneration.The American Journal of Physiology 269 F274-281,1995. 

Cojocel C, Smith JH, Malta K, Sleight SD, Hook JB. Renal protein degradation a biochemical target of specific nephrotoxicants. Fund AppIToxicol 1983 3 278-284. 

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