RT Journal Article
SR Electronic
T1 Metabolism and toxicity of 2-bromo-(diglutathion-S-yl)-hydroquinone and 2-bromo-3-(glutathion-S-yl)hydroquinone in the in situ perfused rat kidney.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 503
OP 510
VO 22
IS 4
A1 M I Rivera
A1 L M Hinojosa
A1 B A Hill
A1 S S Lau
A1 T J Monks
YR 1994
UL http://dmd.aspetjournals.org/content/22/4/503.abstract
AB 2-Br-(diglutathion-S-yl)hydroquinone (2-Br-(diGSyl)HQ) is a potent nephrotoxicant, causing glucosuria, enzymuria, proteinuria, elevations in blood urea nitrogen, and severe histological alterations to renal proximal tubules at doses of 10-15 mumol/kg. In contrast, 2-Br-3-(glutathion-S-yl)hydroquinone (2-Br-3-(GSyl)HQ) is substantially less nephrotoxic than 2-Br-(diGSyl)HQ and requires a dose of at least 50 mumol/kg to cause modest elevations in blood urea nitrogen concentrations. The reason or reasons for this difference in potency is unclear, but since inhibition of renal gamma-glutamyl transpeptidase (gamma-GT) prevents 2-Br-(diGSyl)HQ-mediated nephrotoxicity, metabolism of these conjugates by the kidney must play an important role. To address this question we have compared the metabolism and toxicity of 2-Br-(diGSyl)HQ and 2-Br-3-(GSyl)HQ in the in situ perfused rat kidney (ISPRK). Following infusion of 20 mumol 2-Br-3-(GSyl)HQ into the right renal artery of male Sprague Dawley rats, a total of 23.5 +/- 1.9% (mean +/- SE) of the dose was accounted for in urine and bile over a period of 180 min. 2-Bromo-3-(cystein-S-yl)hydroquinone and 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone were identified in urine, and unchanged 2-Br-3-(GSyl)HQ was identified in urine and bile. The product arising from the oxidative cyclization of 2-bromo-3-(cystein-S-glycine)hydroquinone, 2H-(3-glycine)-7-hydroxy-8-bromo-1,4-benzothiazine, was also identified in urine.(ABSTRACT TRUNCATED AT 250 WORDS)