Metabolism and excretion of S-conjugates derived from hexachlorobutadiene in the isolated perfused rat kidney.
Renal processing of the S-conjugates derived from hexachlorobutadiene (HCBD), S-(pentachlorobutadienyl)glutathione (PCBG), and S-(pentachlorobutadienyl)-L-cysteine (PCBC) was studied in the isolated perfused rat kidney. At an initial perfusate concentration of 20 microM, both conjugates were rapidly eliminated from the perfusate. Calculation of the fractional clearance rates revealed the dominant role of nonfiltering mechanisms in this process. This was confirmed by the strong inhibitory effect of 50 microM probenecid. S-(Pentachlorobutadienyl)-N-acetyl-L-cysteine (N-Ac-PCBC) was detected as the major metabolite of both PCBG and PCBC in urine and perfusate. PCBC and S-(pentachlorobutadienyl)cysteinylglycine were minor urinary metabolites formed from PCBG; only N-Ac-PCBC and PCBC were detected in the perfusate. At an initial S-conjugate concentration of 100 microM in the perfusate, the rate of elimination of both PCBG and PCBC continuously decreased during the perfusion, mainly as the result of a reduced excretion of N-Ac-PCBC. This indicates marked disturbance of N-acetylation and/or transport under these conditions. Addition of probenecid resulted in a significantly reduced renal elimination of both S-conjugates, predominantly due to a reduced rate of mercapturate excretion. In contrast, the nephrotoxicity of PCBC or PCBG was not significantly influenced by probenecid. It is concluded from these experiments that the kidney has the capacity to metabolize HCBD S-conjugates and that nonfiltering excretion of the mercapturic acid plays a decisive role. The pathways of HCBD S-conjugate metabolism in the kidney were shown to be dependent on their initial concentrations in the perfusate, most probably as a consequence of concentration-dependent toxic disturbances of transport and/or N-acetylation.
Institut für Toxikologie, Universität Würzburg, Federal Republic of Germany.
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Schrenk
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Henschler
D000107:Acetylation; D000818:Animals; D002070:Butadienes / Q000378:metabolism* / Q000633:toxicity; D003545:Cysteine / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D010477:Perfusion; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D002070:Butadienes; C050500:S-(1,2,3,4,4-pentachloro-1,3-butadienyl)glutathione; C001335:hexachlorobutadiene; D005978:Glutathione; D003545:Cysteine; D011339:Probenecid