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 γ-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 μmol/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, and 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.
ASJC Scopus subject areas