Persistent Link:
http://hdl.handle.net/10150/186437
Title:
BIOTRANSFORMATION AND NEPHROTOXICITY OF HALOGENATED ETHYLENES.
Author:
HASSALL, CHRISTOPHER DONALD.
Issue Date:
1983
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Haloalkenes were shown to react with cysteine, N-acetyl cysteine, or glutathione to form halogenated vinylthio (HVT) or saturated conjugates. When HVT were administered iv to rabbits, active transport in the renal tubules was inhibited 50% at doses as low as 20 mg/kg within 1 hr after dosing. There was sloughing of the renal brush border membrane with the injury progressing to a specific renal tubular necrosis of the S₃ segment. In vitro studies with renal tubules found that the HVT produced a dose-response related inhibition of acid/base transport, with complete inhibition of transport occurring at 1 mM. The cysteine conjugate synthesized from trichloroethylene, DCVC, inhibited tubular active transport 60 min after in vivo dosing (20-100 mg/kg), 45 min after exposure in the isolated perfused kidney (0.01-1 mM) and 15 min after incubation with isolated tubules (0.01-1 mM). All HVT conjugates had a similar potency with regard to transport inhibition in isolated tubules, with complete inhibition occurring at 1 mM within 15 min for cysteine conjugates compared to 45-60 min for the N-acetyl cysteine or glutathione conjugates. These latter conjugates are thought to be bioactivated to the cysteine conjugate prior to transport inhibition. Inhibition of tubular (gamma)-glutamyl transpeptidase by 1 mM AT-125 or 20 mM serine/borate prevented the inhibition of acid/base transport by the glutathione conjugate. In addition, the sequential formation of glutamate, glycine and the vinyl cysteine conjugate after tubule incubation with the glutathione conjugate provides further evidence for this bioactivation. The cysteine conjugates are thought to be further metabolized in tubules to a toxic intermediate by a brush border localized enzyme, C-S lyase. The inhibitor effect of this intermediate on acid/base transport is reversed in the presence of, or subsequent addition of, 6 mM exogenous glutathione. These studies provide further evidence for the nephrotoxicity of HVT, and formation of the nephrotoxic cysteine conjugates from glutathione and cysteine conjugates. The formation of saturated conjugates from CTFE was also demonstrated. These saturated and/or unsaturated conjugates may be responsible for haloalkene-induced nephrotoxicity.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Halocarbons -- Toxicology.; Ethylene compounds -- Toxicology.; Renal tubular transport.; Kidney tubules.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleBIOTRANSFORMATION AND NEPHROTOXICITY OF HALOGENATED ETHYLENES.en_US
dc.creatorHASSALL, CHRISTOPHER DONALD.en_US
dc.contributor.authorHASSALL, CHRISTOPHER DONALD.en_US
dc.date.issued1983en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractHaloalkenes were shown to react with cysteine, N-acetyl cysteine, or glutathione to form halogenated vinylthio (HVT) or saturated conjugates. When HVT were administered iv to rabbits, active transport in the renal tubules was inhibited 50% at doses as low as 20 mg/kg within 1 hr after dosing. There was sloughing of the renal brush border membrane with the injury progressing to a specific renal tubular necrosis of the S₃ segment. In vitro studies with renal tubules found that the HVT produced a dose-response related inhibition of acid/base transport, with complete inhibition of transport occurring at 1 mM. The cysteine conjugate synthesized from trichloroethylene, DCVC, inhibited tubular active transport 60 min after in vivo dosing (20-100 mg/kg), 45 min after exposure in the isolated perfused kidney (0.01-1 mM) and 15 min after incubation with isolated tubules (0.01-1 mM). All HVT conjugates had a similar potency with regard to transport inhibition in isolated tubules, with complete inhibition occurring at 1 mM within 15 min for cysteine conjugates compared to 45-60 min for the N-acetyl cysteine or glutathione conjugates. These latter conjugates are thought to be bioactivated to the cysteine conjugate prior to transport inhibition. Inhibition of tubular (gamma)-glutamyl transpeptidase by 1 mM AT-125 or 20 mM serine/borate prevented the inhibition of acid/base transport by the glutathione conjugate. In addition, the sequential formation of glutamate, glycine and the vinyl cysteine conjugate after tubule incubation with the glutathione conjugate provides further evidence for this bioactivation. The cysteine conjugates are thought to be further metabolized in tubules to a toxic intermediate by a brush border localized enzyme, C-S lyase. The inhibitor effect of this intermediate on acid/base transport is reversed in the presence of, or subsequent addition of, 6 mM exogenous glutathione. These studies provide further evidence for the nephrotoxicity of HVT, and formation of the nephrotoxic cysteine conjugates from glutathione and cysteine conjugates. The formation of saturated conjugates from CTFE was also demonstrated. These saturated and/or unsaturated conjugates may be responsible for haloalkene-induced nephrotoxicity.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHalocarbons -- Toxicology.en_US
dc.subjectEthylene compounds -- Toxicology.en_US
dc.subjectRenal tubular transport.en_US
dc.subjectKidney tubules.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.identifier.proquest8319720en_US
dc.identifier.oclc689058362en_US
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