Role of in vivo cysteine conjugate ß-lyase inhibition on nephrotoxicity due to 1,2-dichloropropane in vivo and in vitro

“In vivo” and “in vitro” pretreatment with aminooxyacetic acid (AOAA), a specific inhibitor of renal cysteine conjugate ß-lyase (ß-lyase) activity, protects against S-conjugates-induced nephrotoxicity. In order to study “in vivo” and “in vitro” nephrotoxic effects of 1,2-dichloropropane (DCP), male Wistar rats were given AOAA 0.5 mmole/kg i.p. 1 hour before “in vivo” treatment with DCP (4.4 mmoles/kg i.p.), or the sacrifice for “in vitro” studies carried out by means of the renal cortical slice model. DCP concentration of 25x10-3 M was used for “in vitro” experiments. “In vivo” DCP-treated rats were sacrificed ten hours after dosing, because preliminary experiments showed the maximum reduced glutathione depletion after this time. DCP “in vivo” treatment caused a significant (p<0.005) loss of organic anion accumulation (measured by means of p-aminohippurate), increase of blood urea nitrogen (p<0.05) and urinary protein excretion (p<0.001); “in vitro” treatment caused a significant lipid peroxidation (p<0.001), measured by means of malondialdehyde release in the incubation medium, and loss of organic anion accumulation (p<0.001). AOAA pretreatment prevents “in vivo” and “in vitro” DCP nephrotoxicity almost totally. Data show that DCP-induced nephrotoxicity is via the mercapturic acid pathway with activation of the cysteine conjugate to a nephrotoxic thiol, and confirm our previous research “in vitro” that also haloalkane nephrotoxicity may be mediated via ß-lyase activation.