Site-Specific Nephrotoxicity

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. 

Precocenes may not provide the new approach to insect control originally expected ("4th generation" insecticides, 9) because they are not active in some major groups of agricultural pests (Lepidoptera) and because their mode of action (cytotoxicity) is not compatible with environmental concerns. Indeed, precocene II has been shown to be hepatotoxic and nephrotoxic in rats (16, 17). However, research on precocenes has led to (at least) two Important conclusions (1) compounds structurally unrelated to the JH biosynthetic pathway can reach critical sites (e.g. epoxidase) within the CA, and (2) such compounds can be catalytically processed (e.g. epoxidlzed) by enzymes of JH biosynthesis. The lax substrate specificity of methyl farnesoate epoxidase in the corpora allata and its catalytic competence might be exploited in the design of irreversible Inhibitors of JH biosynthesis (Figure 1). 

ATP is uncoupled from electron transport. Other compounds affect mitochondrial function by inhibiting the electron transport chain at one or more specific sites, such as the toxic metabolite of MPTP which inhibits complex I (see Chapter 7). The toxic metabolite of hexachlorobutadiene is believed to be nephrotoxic due to inhibition of mitochondria function in the proximal tubular cells. 

Advantages of in vitro models include the ability to carefully modulate exposure conditions and dissect mechanisms of action. Unlike studies in laboratory animals, in vitro models enable the use of paired controls and treated samples from the same set of incubations. Another advantage specifically for studies of renal function and nephrotoxicity is that in vitro models can be constructed that derive from specific nephron segments, thereby allowing study of effects at the specific sites in the kidneys where they occur. 

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