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.