Effect of inhibition of gamma-glutamyltranspeptidase on biliary and urinary excretion of glutathione-derived thiols and methylmercury.
Acivicin (AT-125; 6.25-200 mumol/kg i.v.) inhibited hepatic, biliary and renal gamma-glutamyltranspeptidase (GGT) activity up to 88, 99 and 97%, respectively, in 4-week-old rats. This inhibition of GGT by acivicin resulted in a 10- to 12-fold increase in the biliary excretion of reduced (GSH) and oxidized glutathione. Because the biliary excretion of cysteinylglycine (Cys-Gly), Cys-Gly disulfide, cysteine (Cys) and cystine concomitantly decreased (63-99%), the biliary excretion rate of total glutathione-derived thiols and disulfides did not change. In contrast, acivicin treatment dramatically elevated the urinary excretion rate of glutathione-derived thiols in a dose-dependent fashion, resulting in a 390-fold increase at the highest dosage. This mainly originated from enhancement of urinary excretion of GSH (up to 7200-fold), although the excretion of Cys and Cys-Gly into urine was also increased. Acivicin treatment did not affect hepatic and renal levels of GSH but, at high dosages, reduced the concentration of Cys in these organs. GSH and oxidized glutathione concentrations in serum were increased, whereas cystine was diminished in acivicin-treated rats. Inhibition of GGT by acivicin (100 mumol/kg i.v.) failed to influence the biliary excretion of methylmercury but increased urinary excretion 34-fold. Even though the urinary thiol excretion was much higher than the biliary thiol excretion in the acivicin-treated rats, methylmercury was preferentially excreted into bile rather than urine, indicating the importance of the liver as an excretory organ for methylmercury.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001646:Bile / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism / Q000652:urine; D005978:Glutathione / Q000378:metabolism* / Q000652:urine; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D008767:Methylmercury Compounds / Q000378:metabolism* / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000378:metabolism / Q000652:urine; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors*
D004220:Disulfides; D007555:Isoxazoles; D008767:Methylmercury Compounds; D013438:Sulfhydryl Compounds; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin