Species differences in renal gamma-glutamyl transpeptidase activity do not correlate with susceptibility to 2-bromo-(diglutathion-S-yl)-hydroquinone nephrotoxicity.
Administration of 2-bromo-(diglutathion-S-yl)hydroquinone (2-Br-[diGSyl]HQ) (10-30 mumol/kg; i.v.) to rats causes severe renal proximal tubular necrosis. gamma-Glutamyl transpeptidase (gamma-GT) catalyses the first step in the metabolism of glutathione (GSH) and its S-conjugates and the toxicity of 2-Br-(diGSyl)HQ can be emeliorated by inhibition of renal gamma-GT. Species differences in the specific activity of renal gamma-GT have been reported and we now describe the relationship between renal gamma-GT and species differences in susceptibility to 2-Br-(diGSyl)HQ nephrotoxicity. Although rats exhibited the highest specific activity of renal gamma-GT, and were the most sensitive species toward 2-Br-(diGSyl)HQ-mediated nephrotoxicity, renal gamma-GT activity did not correlate with susceptibility in the other species examined. Indeed, the guinea pig, which expressed the lowest activity of renal gamma-GT between the species (8% of the rat) was the only other rodent found to be responsive toward 2-Br-(diGSyl)HQ at the highest dose tested (200 mumol/kg; intracardiac). Thus, factors other than gamma-GT activity probably play an important role in modulating species susceptibility to 2-Br-(diGSyl)HQ nephrotoxicity. Although the reason(s) for the interspecies variation in response to 2-Br-(diGSyl)HQ are unclear at present, it seems possible that differences in both renal biochemistry, such as differences in the relative activities of cysteine conjugate N-acetyl transferase and deacetylase, and renal physiology, contribute to the observed results.
Lau
S S
SS
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.
Jones
T W
TW
Sioco
R
R
Hill
B A
BA
Pinon
R K
RK
Monks
T J
TJ
D000818:Animals; D006224:Cricetinae; D005978:Glutathione / Q000031:analogs & derivatives* / Q000633:toxicity; D006168:Guinea Pigs; D006873:Hydroquinones / Q000633:toxicity*; D007672:Kidney Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D007674:Kidney Diseases / Q000139:chemically induced; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D013045:Species Specificity; D005723:gamma-Glutamyltransferase / Q000378:metabolism*
D006873:Hydroquinones; C066791:2-bromo-(diglutathion-S-yl)hydroquinone; C042377:2-bromohydroquinone; D005723:gamma-Glutamyltransferase; D005978:Glutathione