The in vivo disposition of 2-bromo-[14C]hydroquinone and the effect of gamma-glutamyl transpeptidase inhibition.

Abstract

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.

• Authors: S S Lau, T J Monks
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 103 Issue 1 Pg. 121-32 (Mar 15 1990) ISSN: 0041-008X [Print] United States
• PMID: 1969181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Hydroquinones
• Isoxazoles
• Oxazoles
• 2-bromohydroquinone
• gamma-Glutamyltransferase
• Glutathione
• acivicin

Topics

• Animals
• Catheterization
• Glutathione (metabolism)
• Hydroquinones (metabolism, toxicity)
• Isoxazoles (pharmacology)
• Kidney (drug effects, metabolism)
• Male
• Oxazoles (pharmacology)
• Rats
• Rats, Inbred Strains
• gamma-Glutamyltransferase (analysis, antagonists & inhibitors)