The in vivo disposition of 2-bromo-[14C]hydroquinone and the effect of gamma-glutamyl transpeptidase inhibition.
We have previously shown that the renal necrosis observed after 2-bromohydroquinone (2-BrHQ) administration to rats is probably caused by the formation of 2-Br-(diglutathion-S-yl)HQ (2-Br-[diGSyl]HQ), since injection of this conjugate caused severe proximal tubular necrosis. In the present study we report the in vivo metabolism and covalent binding of 2-[14C]-BrHQ in male Sprague-Dawley rats. The major urinary and biliary metabolite was a glucuronide conjugate. In addition, 2-Br-(di-GSyl)HQ, 2-Br-3-(GSyl)HQ, 2-Br-5-(GSyl)HQ, and 2-Br-6-(GSyl)HQ were all detected as urinary and biliary metabolites of 2-BrHQ. The in vivo covalent binding of 2-[14C]BrHQ to kidney, pancreas, seminal vesicles, intestine, bone marrow, and liver was 21.8, 1.5, 1.2, 4.4, 1.8, and 2.6 nmol/mg protein, respectively. gamma-Glutamyl transpeptidase (gamma-GT) activity measured in these tissues was 947, 159, 55, 31 and 5.5 U/mg. Liver gamma-GT activity was negligible (0.07 U/mg). Thus, maximum covalent binding and gamma-GT activity occurred in the kidney. Renal covalent binding and gamma-GT activity were positively correlated with nephrotoxicity. Pretreatment of rats with L(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazole-acetic acid (AT-125) inhibited renal gamma-GT, after 24 hr, by 76%, renal covalent binding by 73%, and 2-BrHQ-mediated nephrotoxicity, as assessed by elevations in blood urea nitrogen (BUN), by 70%. These alterations were accompanied by an increase in the urinary excretion of each of the GSH conjugates, an increase in the fecal excretion of total radioactivity, and a decrease in plasma radioactivity at 24 hr. The present data provide evidence that 2-BrHQ is metabolized in vivo to nephrotoxic GSH conjugates. In addition, AT-125 probably inhibits nephrotoxicity by decreasing the gamma-GT-mediated renal proximal tubule accumulation of the toxic metabolites, thereby facilitating their excretion into urine. Although AT-125 inhibited extrarenal gamma-GT activity by 34-77%, it had variable effects on extrarenal covalent binding. Whereas covalent binding to renal tissue is probably mediated by reactive metabolites of the isomeric 2-Br-(GSyl)HQ conjugates, binding to extrarenal tissue may be mediated by both the conjugates and by 2-bromohydroquinone per se.
Lau
S S
SS
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.
Monks
T J
TJ
D000818:Animals; D002404:Catheterization; D005978:Glutathione / Q000378:metabolism; D006873:Hydroquinones / Q000378:metabolism* / Q000633:toxicity; D007555:Isoxazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010080:Oxazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D005723:gamma-Glutamyltransferase / Q000032:analysis / Q000037:antagonists & inhibitors*
D006873:Hydroquinones; D007555:Isoxazoles; D010080:Oxazoles; C042377:2-bromohydroquinone; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin