Inhibition of gamma-glutamyl transpeptidase potentiates the nephrotoxicity of glutathione-conjugated chlorohydroquinones.
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 mumol/kg; iv) renal proximal tubular necrosis, as evidenced by elevations in blood urea nitrogen (BUN), and in the urinary excretion of lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (gamma-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 gamma-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 gamma-GT constitutes a detoxication reaction.
Mertens
J J
JJ
Department of Toxicology, Agricultural University Wageningen, The Netherlands.
Temmink
J H
JH
van Bladeren
P J
PJ
Jones
T W
TW
Lo
H H
HH
Lau
S S
SS
Monks
T J
TJ
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D002703:Chloranil / Q000031:analogs & derivatives* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004563:Electrochemistry; D005978:Glutathione / Q000031:analogs & derivatives* / Q000633:toxicity; D007555:Isoxazoles / Q000494:pharmacology; D007672:Kidney Cortex / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors*
D007555:Isoxazoles; D002703:Chloranil; C057105:2-gluthionyl-3,5,6-trichloro-1,4-benzoquinone; C069711:2,5-dichloro-3-(glutathionyl-S-yl)-1,4-benzoquinone; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C006303:acivicin; D001205:Ascorbic Acid