Glutathione conjugates of 2-bromohydroquinone are nephrotoxic.
Incubation of either o-bromophenol or 2-bromohydroquinone with rat liver microsomes and 0.25 mM 35S-glutathione (GSH) gave rise to several isomeric 35S-GSH conjugates. A mixture of these isomeric GSH conjugates was prepared chemically and two were purified by HPLC; 1H-NMR spectroscopy revealed that one was 2-bromo-3-(glutathion-S-yl)hydroquinone and the other was a disubstituted GSH conjugate which could be either 2-bromo-3,5-(diglutathion-S-yl)hydroquinone or 2-bromo-3,6-(diglutathion-S-yl)hydroquinone. Injection of the disubstituted GSH conjugate intravenously to rats caused substantial elevations in blood urea nitrogen levels. Treatment of rats with AT-125 (Acivicin; NSC 163501; 10 mg/kg ip) caused a substantial inhibition of kidney gamma-glutamyl transpeptidase activity and decreased 2-bromohydroquinone-mediated elevations in blood urea nitrogen. These findings are consistent with the view that the kidney necrosis observed after administration of either bromobenzene (1), o-bromophenol (2), or 2-bromohydroquinone (3) might be due in part to 2-bromohydroquinone GSH conjugates formed in the liver and subsequently transported to the kidney and converted to ultimate nephrotoxic metabolite(s).
Monks
T J
TJ
Lau
S S
SS
Highet
R J
RJ
Gillette
J R
JR
D000818:Animals; D003545:Cysteine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006873:Hydroquinones / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010636:Phenols / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D005723:gamma-Glutamyltransferase / Q000502:physiology
D006873:Hydroquinones; D010636:Phenols; C042377:2-bromohydroquinone; C032038:2-bromophenol; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D003545:Cysteine