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Inhibition of γ-glutamyl transpeptidase potentiates the nephrotoxicity of glutathione-conjugated chlorohydroquinones

1991; Elsevier BV; Volume: 110; Issue: 1 Linguagem: Inglês

10.1016/0041-008x(91)90288-p

1096-0333

J.J.W.M. Mertens, J.H.M. Temmink, Peter J. van Bladeren, Thomas W. Jones, Herng‐Hsiang Lo, Serrine S. Lau, Terrence J. Monks,

Nitric Oxide and Endothelin Effects

Administration of either 2,5-dichloro-3-(glutathion-S-yl)-1,4-benzoquinone (DC-[GSyl]BQ) or 2,5,6-trichloro-3-(glutathion-S-yl)-1,4-benzoquinone (TC-[GSyl]BQ) to male Sprague-Dawley rats caused dose-dependent (50–200 μmol/kg; iv) renal proximal tubular necrosis, as evidenced by elevations in blood urea nitrogen (BUN), and in the urinary excretion of lactate dehydrogenase (LDH), γ-glutamyl transpeptidase (γ-GT) and glucose. Renal proximal tubular necrosis was also confirmed by histological examination of kidney slices prepared from DC-(GSyl)BQ- and TC-(GSyl)BQ-treated animals. Administration of the corresponding hydroquinone conjugates (DC-[GSyl]HQ and TC-[GSyl]HQ), prepared by reducing the quinones with a threefold molar excess of ascorbic acid, resulted in a substantial increase in nephrotoxicity. Moreover, in contrast to other glutathione (GSH)-conjugated hydroquinones, the nephrotoxicity of both DC-(GSyl)HQ and TC-(GSyl)HQ was potentiated when rats were pretreated with AT-125, an irreversible inhibitor of γ-GT. Neither the quinone-GSH nor the hydroquinone-GSH conjugates caused any effect on liver histology or serum glutamate-pyruvate transaminase levels. The results suggest that coadministration of ascorbic acid with DC-(GSyl)BQ or TC-(GSyl)BQ decreases their interactions with extrarenal nucleophiles, including plasma proteins, and thus increases the concentration of the conjugates delivered to the kidney, and hence toxicity. Furthermore the ability of AT-125 to potentiate the nephrotoxicity of DC-(GSyl)HQ and TC-(GSyl)HQ suggests that metabolism of these conjugates by γ-GT constitutes a detoxication reaction.