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. 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. 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. 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.

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Sex- and age-related nephrotoxicity due to 1,2-dichloropropane was studied in vitro by means of renal cortical slices obtained from Wistar rats. Reduced glutathione content, organic anion accumulation (p-aminohippurate), and release of malondialdehyde (to measure the extent of lipid peroxidation), aspartate aminotransferase, gamma-glutamyltransferase and lactate dehydrogenase into the incubation medium were determined. Sex differences in naive rats parameters were slight, but male were more susceptible to toxic effects of 1,2-dichloropropane than female rats; glutathione depletion, lipid peroxidation, and loss of organic anion accumulation were higher in male than in female slices. During senescence, naive male rats showed a progressive decrease of glutathione content (statistically significant from 7-9 months of age), increase of spontaneous lipid peroxidation from the same age, and increase of signs of cytotoxicity (release of aspartate aminotransferase and lactate dehydrogenase into the incubation medium) from 3-4 months of age. A loss of organic anion accumulation started from 7-9 months of age. Slices from rats of 3-4 months old showed the apparently highest susceptibility to 1,2-dichloropropane but depletion of glutathione content and loss of organic anion accumulation were at the same level in the oldest rats. The age decrease of control values caused the differences in the percentage ratio and then, apparently, a lower DCP effect. On the contrary, the increase of aspartate aminotransferase released in the incubation medium by DCP-treated slices corresponded to the age-related increase in cytotoxicity.

The in vitro renal cortical slice model was used to study: 1) the effects on the kidney of some haloalkanes and haloalkenes using 3-month-old male Wistar rats; 2) influence of age and sex on renal cortical slice indices in non-treated rats; and 3) effects of 1,2-dichloropropane on the slices after pretreatment of 3-month-old male Wistar rats with DL-butathionine-[S,R]-sulphoximine. The most nephrotoxic chemical used was 1,3-dichloropropene, which caused a total depletion in the levels of reduced glutathione, a high peroxidation of lipid (about three thousand-fold with respect to control), a significant release of tubular enzymes into the medium, and loss of organic anion ( p-aminohippurate) accumulation. All the chemicals affected the cytosol more than the brush border. The most remarkable age-related differences in the untreated slices were the progressive decrease of reduced glutathione (p<0.05 from three months of age), and an increase in lactate dehydrogenase release into the medium (p<0.05 from six months of age). By contrast, sex differences were slight. The ‘treatment with 1,2-dichloropropane of slices prepared from rats pretreated with DL-butathionine-[S,R]-sulphoximine significantly increased the depletion of glutathione content (p<0.05) and malondialdehyde release in the medium (p<0.001) caused by the solvent alone.