Assessment of the role of glutathione conjugation in the protection afforded by anethol dithiolthione against hexachloro-1,3-butadiene-induced nephrotoxicity.
Administration of anethol dithiolthione (ADT) to rodents can afford protection against some chemically induced toxicities. The aim of the present study was to assess the effects of ADT on hexachloro-1,3-butadiene (HCBD)-induced nephrotoxicity in the rat and to determine the mechanism of its action. Renal integrity was evaluated by measuring urinary excretion of glucose, protein, and gamma-glutamyl transpeptidase and by histological evaluation. A 3-day pretreatment with ADT (300 mg/kg/day) protected against the toxicity of various doses of HCBD (ranging from 15.6 to 62.5 mg/kg). The pretreatment increased (1.4-fold) the nonprotein sulfhydryl content (NPSH) of the liver. However, it did not modify the biliary excretion of radiolabeled materials in [14C]HCBD- treated (20 mg/kg) rats, nor that of the bioactivated HCBD metabolite, S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-glutathione (PCBG). Moreover, ADT pretreatment protected rats against the nephrotoxicity induced by PCBG (20 mg/kg) itself. The extent of covalent binding to kidney proteins of [14C]HCBD-derived metabolites was not modified by pretreatment with ADT. Incubation of rat kidney cortical slices in a medium containing 0.1 mM of the nephrotoxic glutathione (PCBG) or cysteine (PCBC, S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine) conjugates of HCBD for 30 min resulted in a 75% reduction in the slice/medium ratio of p-aminohipurate (PAH) compared to that seen in controls. When the cortical slices were incubated with ADT (30 min, 0.2 mM) prior to incubation with the nephrotoxic conjugates, the reduction was only 33%. Neither the in vitro nor the in vivo treatments did modify the activity of renal cytosolic beta-lyase; however, the latter treatment caused an increase in NPSH content. A 15-min incubation of kidney cortical slices with glutathione (10 mM) resulted in a 5-fold increase of NPSH, but failed to prevent the reduction in PAH uptake caused by PCBG and PCBC. Altogether, the in vivo and renal slice data suggest that ADT protects rats against HCBD-induced nephrotoxicity by a mechanism that does not involve the modulation of HCBD conjugation with liver GSH, nor the modulation of the kidney NPSH level and beta-lyase activity. The mechanism of protection conferred to rats by an ADT pretreatment against HCBD-induced nephrotoxicity appears to take place in the kidney at a step beyond the generation of ultimate toxic metabolites derived from PCBC.
Bouthillier
L
L
Université de Montréal, Département de médecine du travail et d'hygiène du mileu, Québec, Canada.
Charbonneau
M
M
Brodeur
J
J
D000781:Anethole Trithione / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D002070:Butadienes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D002756:Cholagogues and Choleretics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D003545:Cysteine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D006029:Glycosuria; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008190:Lyases / Q000378:metabolism; D011507:Proteinuria; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000652:urine; D010130:p-Aminohippuric Acid / Q000378:metabolism
D002070:Butadienes; D002756:Cholagogues and Choleretics; D005659:Fungicides, Industrial; D013438:Sulfhydryl Compounds; C039961:S-(1,2-dichlorovinyl)cysteine; C039330:S-pentachlorobuta-1,3-dien-yl-cysteine; C001335:hexachlorobutadiene; D005723:gamma-Glutamyltransferase; D008190:Lyases; D005978:Glutathione; D003545:Cysteine; D000781:Anethole Trithione; D010130:p-Aminohippuric Acid