Figure 1516

This figure illustrates the renal proximal tubular uptake, biotransformation, and toxicity of glutathione and cysteine conjugates and mer-capturic acids of haloalkanes and haloalkenes (R). 1) Formation of a glutathione conjugate within the renal cell (R-SG). 2) Secretion of the R-SG into the lumen. 3) Removal of the ^-glutamyl residue (7-Glu) by 7-glutamyl transferase. 4) Removal of the glycinyl residue (Gly) by a dipeptidase. 5) Luminal uptake of the cysteine conjugate (R-Cys). Basolateral membrane uptake of R-SG (6), R-Cys (7), and a mercap-turic acid (N-acetyl cysteine conjugate; R-NAC)(8). 9) Secretion of R-NAC into the lumen. 10) Acetylation of R-Cys to form R-NAC. 11) Deacetylation of R-NAC to form R-Cys. 12) Biotransformation of the penultimate nephrotoxic species (R-Cys) by cysteine conjugate P-lyase to a reactive intermediate (R-SH), ammonia, and pyruvate. 13) Binding of the reactive thiol to cellular macromolecules (eg, lipids, proteins) and initiation of cell injury. (Adapted from Monks and Lau [5]; with permission.)

Representative starting Submitochondrial fractions material A. Untreated B. TFEC (30 mg/kg)

Representative starting Submitochondrial fractions material A. Untreated B. TFEC (30 mg/kg)

Covalent binding of a nephrotoxicant metabolite in vivo to rat kidney tissue, localization of binding to the mitochondria, and identification of three proteins that bind to the nephrotoxicant. A, Binding of tetrafluo-roethyl-L-cysteine (TFEC) metabolites in vivo to rat kidney tissue detected immunohisto-chemically. Staining was localized to the S3 segments of the proximal tubule, the segment that undergoes necrosis. B, Immunoreactivity in untreated rat kidneys. C, Isolation and fractionation of renal cortical mitochondria from untreated and TFEC treated rats and immunoblot analysis revealed numerous proteins that bind to the nephrotoxicant (innerinner membrane, matrix-soluble matrix, outer-outer membrane, inter-intermembrane space). The identity of three of the proteins that bound to the nephrotoxicant: P84, mortalin (HSP70-like); P66, HSP 60; and P42, aspartate aminotransferase. Mr—relative molecular weight. (From Hayden et al. [6], and Bruschi et al. [7]; with permission.)

Lipid peroxidation and mitochondrial dysfunction

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