Role of metabolic activation in the toxicity of S-(pentachlorobutadienyl)glutathione and S- (pentachlorobutadienyl)- l -cysteine in the isolated perfused rat kidney.
The nephrotoxicity of hexachlorobutadiene (HCBD) has been attributed to a sequence of metabolic steps initiated by conjugation of the haloalkene with glutathione in the liver. Current evidence suggests that the conjugate S-(pentachlorobutadienyl)glutathione (PCBG) thus formed is degraded in the kidney by dipeptidase(s) to the cysteinylglycinyl conjugate. Subsequent hydrolysis by γ-glutamyltranspeptidase (GGT) leads to the cysteine conjugate S- (pentachlorobutadienyl)- l -cysteine (PCBC), which is cleaved by cysteine conjugate β-lyase to pyruvate, ammonia and a reactive thiol, which is presumed to induce nephrotoxicity and nephrocarcinogenicity. In the isolated perfused rat kidney PCBG produced concentration-dependent nephrotoxicity as indicated by the occurrence in the urine of alkaline phosphatase and GGT and by the impairment of glucose reabsorption. The nephrotoxicity of PCBG was blocked by the specific GGT inhibitor, AT-125 (L-αS,5S)-αamino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) and by aminooxyacetic aid (AOAA), an inhibitor of β-lyase. PCBC, A presumptive intermediate in the metabolic activation of PCBG, caused a rapid onset of massive nephrotoxicity which was blocked effectively by AOAA. At 0.1 mm-PCBC the increase in biochemical parameters of nephrotoxicity was accompanied by massive tubular necrosis. It is concluded that the glutathione conjugate of HCBD is metabolized within the target organ, the kidney, to PCBC, which is activated by renal β-lyase to a highly nephrotoxic intermediate.
Schrenk
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Institut für Toxikologie, Universität Würzburg, D-8700 Würzburg, Federal Republic of Germany.
Dekant
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Wünsch
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Henschler
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