TY - JOUR
T1 - Inhibition of γ-glutamyl transpeptidase potentiates the nephrotoxicity of glutathione-conjugated chlorohydroquinones
AU - Mertens, Jos J.W.M.
AU - Temmink, Johan H.M.
AU - van Bladeren, Peter J.
AU - Jones, Thomas W.
AU - Lo, Herng Hsiang
AU - Lau, Serrine S.
AU - Monks, Terrence J.
N1 - Funding Information:
’ This work was supported in part by USPHS Awards ES 04662 (T.J.M.) and GM 39338 (S.S.L.), NATO Collaborative Research Award 542/87, and the Ministry of Education and Sciences in The Netherlands. ’ Present address and to whom all correspondence should be addressed Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX 787 12.
PY - 1991/8
Y1 - 1991/8
N2 - 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.
AB - 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.
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U2 - 10.1016/0041-008X(91)90288-P
DO - 10.1016/0041-008X(91)90288-P
M3 - Article
C2 - 1678558
AN - SCOPUS:0025875883
SN - 0041-008X
VL - 110
SP - 45
EP - 60
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 1
ER -