In-Vitro Mechanisms of 1,2-Dichloropropane Nephrotoxicity using the Renal Cortical Slice Model

Abstract

<jats:p> 1 Renal cortical slices isolated from the kidneys of male Wistar rats were used as an experimental model for studying the nephrotoxicity induced by 1,2-dichloropropane. </jats:p><jats:p> 2 The solvent causes a depletion of renal reduced glutathione content and slight, but significant, lipid peroxidation. The block of the oxidative pathway with carbon monoxide prevents glutathione content depletion, and shows that this conjugation is the major step in 1,2-dichloropropane metabolism. </jats:p><jats:p> 3 Loss of organic anion accumulation and release into the incubation medium of tubular enzymes, mainly from the soluble fraction, are the toxic effects of the solvent. The brush border is only slightly affected. </jats:p><jats:p> 4 The mechanism of nephrotoxicity appears to occur via mercapturic acid metabolism. Acivicin and aminooxyacetic acid, inhibitors of gammaglutamyltransferase and β-lyase activity, respectively, partially but significantly prevent the loss of organic anion accumulation induced by 1,2-dichloropropane. Furthermore, α-ketobutyrate, an activator of β-lyase, enhances the effects of 1,2-dichloropropane on the target, but is itself toxic for organic anion accumulation. </jats:p>

A trial to find appropriate animal models of dichloropropane‐induced cholangiocarcinoma based on the hepatic distribution of glutathione S‐transferases

“…In this regard, a previous study showed that DCP-induced GSH depletion was prevented by CO, an inhibitor of P450 in renal cortical slices, and that loss of the anion gap induced by DCP was prevented by inhibitors of γ -glutamyl transferase and β -lyase. These results suggest that DCP nephrotoxicity is probably related to mercapturic acid metabolism after oxidation by P450 20) . Another more recent study also argued for the role of cytochrome P450 2E1 in the initiation of DCP-induced liver damage 21) .…”

Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes

“…reported significantly high AID expression in the epithelial cells of cholangiocarcinoma, with massive inflammation in the surrounding liver tissue ( 48 ). Although the tissue toxicity of 1,2-DCP and DCM has been reported mainly in animal models, and whether they affect biliary epithelia remains unclear ( 49 ), massive fibrosis was observed to surround cancerous and non-cancerous bile ducts in the printing workers’ cholangiocarcinoma samples ( 8 ). Our preliminary immunohistochemistry data suggested that AID was expressed in the transformed epithelial cells of the printing workers’ cholangiocarcinomas (data not shown).…”

Effect of α-Ketobutyrate on Microvascular Thickness in the Diabetic Rat Kidney

“…There is evidence that S-(1,2-dichlorovinyl)-L-homocysteine induces nephrotoxicity, and is metabolized by kidney cytosol to 2-mercaptobenzothiazole with this reaction being enhanced by addition of a-KB, an amino group acceptor (Elfarra et al, 1986). In contrast, a-KB is a specific activator of b-lyase and may cause toxic effects in the kidney as a consequence of enhanced accumulation of organic anions by 1,2-dichloropropane (Trevisan et al, 1993). We observed that a-KB had no adverse effects in non-diabetic rats and were unable to detect any increase of unknown peaks by HPLC.…”