The effects of 2,3,5-(triglutathion-S-yl)hydroquinone on renal mitochondrial respiratory function in vivo and in vitro: possible role in cytotoxicity.
Administration of 2,3,5-(triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] to rats causes severe renal proximal tubular necrosis. Although the cellular target(s) for 2,3,5-(triGSyl)HQ is not known, substantial evidence implicates mitochondria as the primary cellular target for aliphatic S-conjugates. To determine whether mitochondria are targets for 2,3,5-(triGSyl)HQ, the in vivo and in vitro effects of this conjugate on rat renal mitochondria (RRM) were investigated. In vitro exposure of RRM to 2,3,5-(triGSyl)HQ inhibited site I-supported respiration to a much greater extent than site II-supported respiration. Inhibition of mitochondrial function, as manifested by decreases in the respiratory control ratios, were a consequence of significant elevations in state 4 respiration. Inhibition of constitutive gamma-GT activity with AT-125 had no effect on the ability of 2,3,5-(triGSyl)HQ to decrease mitochondrial function. The effects of 2,3,5-(triGSyl)HQ on mitochondrial function in vivo were subsequently assessed. Shortly (0.5-2.0 hr) following administration of 2,3,5-(triGSyl)HQ (20 mumol/kg, iv) to rats, a significant elevation of state 4 respiration was observed. Thereafter (4-16 hr) state 4 respiration returned to control values and state 3 respiration became significantly depressed. A total collapse in RRM function occurred by 24 hr. The effects of 2,3,5-(triGSyl)HQ on state 4 respiration preceded significant elevations in blood urea nitrogen, which occurred at 8 hr. However, pretreatment of animals with probenecid, an inhibitor of organic anion transport, caused a significant decrease in the 2,3,5-(triGSyl)HQ-mediated elevations in state 4 respiration at 1 hr, without preventing the subsequent development of renal necrosis. In contrast, AT-125, which protected animals from 2,3,5-(triGSyl)HQ-mediated nephrotoxicity, had no effect on the early (1 hr) elevations in state 4 respiration but did prevent the later (8 hr) decreases in state 3 respiration. The data suggest that the early elevation in state 4 respiration observed in vivo is unlikely to contribute to 2,3,5-(triGSyl)HQ-mediated nephrotoxicity. The relationship between the decrease in state 3 respiration seen at later time points and the subsequent development of toxicity require further study before a cause and effect relationship can be determined.
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 18712.
B A
BA
Hill
T J
TJ
Monks
S S
SS
Lau
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D006873:Hydroquinones / Q000008:administration & dosage / Q000633:toxicity*; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D010101:Oxygen Consumption; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D005723:gamma-Glutamyltransferase / Q000378:metabolism
D006873:Hydroquinones; C078765:2,3,5-(triglutathion-S-yl)hydroquinone; D005723:gamma-Glutamyltransferase; D005978:Glutathione; D011339:Probenecid