Persistent Link:
http://hdl.handle.net/10150/185495
Title:
Metabolism and bioactivation of 1,2,3-trichloropropane (TCP).
Author:
Weber, Gregory Louis.
Issue Date:
1991
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:
1,2,3-Trichloropropane (TCP) causes rat hepatic DNA damage in the form of DNA single strand breaks. This damage was dose and time dependent. In vivo ¹⁴C-TCP equivalents covalently bound to hepatic protein, RNA and DNA. Glutathione depletion with L-buthionine-(R,S)-sulfoximine increased binding to protein by 342% while it decreased binding to DNA by 56%. The in vivo binding data suggest a dual role for glutathione in the bioactivation of TCP. In vitro rat hepatic microsomes activated TCP to species which covalently bound to microsomal protein. Rat liver microsomes also bioactivated TCP to the direct acting mutagen 1,3-dichloroacetone. 1,3-Dichloroacetone was identified as the major microsomal protein binding species through conjugation with N-acetylcysteine to form 1,3-(2-propanone)-bis-S-(N-acetylcysteine) which accounted for 87% of all TCP microsomal metabolism. These findings support a role for 1,3-dichloroacetone as a mutagenic metabolite of TCP. Carbon-13 nuclear magnetic resonance was used to identify directly the urinary metabolite of ¹³C₃-TCP (99 atom % enrichment). Urine was investigated directly using proton-decoupled ¹³C and two-dimensional homonuclear correlated nuclear magnetic resonance spectroscopy. Spectral shifts have been assigned to N-acetyl-S-(2-hydroxy-3-chloropropyl)cysteine, 1,3-(2-propanol)-bis-S-(N-acetylcysteine), N-acetyl-S-(2-hydroxy-2-carboxyethyl)cysteine, 2,3-dichloropropionic acid, 2-chloroethanol, ethylene glycol and oxalic acid by comparison to spectra of authentic standards. No unchanged TCP was detected. From the results obtained it is concluded that metabolism of TCP by cytochromes P450 and by glutathione conjugation can result in the formation of reactive metabolites of TCP which may be responsible for TCP genotoxicity.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Dissertations, Academic; Genetic toxicology; Toxicology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmacology and Toxicology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Sipes, I. Glenn

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleMetabolism and bioactivation of 1,2,3-trichloropropane (TCP).en_US
dc.creatorWeber, Gregory Louis.en_US
dc.contributor.authorWeber, Gregory Louis.en_US
dc.date.issued1991en_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.abstract1,2,3-Trichloropropane (TCP) causes rat hepatic DNA damage in the form of DNA single strand breaks. This damage was dose and time dependent. In vivo ¹⁴C-TCP equivalents covalently bound to hepatic protein, RNA and DNA. Glutathione depletion with L-buthionine-(R,S)-sulfoximine increased binding to protein by 342% while it decreased binding to DNA by 56%. The in vivo binding data suggest a dual role for glutathione in the bioactivation of TCP. In vitro rat hepatic microsomes activated TCP to species which covalently bound to microsomal protein. Rat liver microsomes also bioactivated TCP to the direct acting mutagen 1,3-dichloroacetone. 1,3-Dichloroacetone was identified as the major microsomal protein binding species through conjugation with N-acetylcysteine to form 1,3-(2-propanone)-bis-S-(N-acetylcysteine) which accounted for 87% of all TCP microsomal metabolism. These findings support a role for 1,3-dichloroacetone as a mutagenic metabolite of TCP. Carbon-13 nuclear magnetic resonance was used to identify directly the urinary metabolite of ¹³C₃-TCP (99 atom % enrichment). Urine was investigated directly using proton-decoupled ¹³C and two-dimensional homonuclear correlated nuclear magnetic resonance spectroscopy. Spectral shifts have been assigned to N-acetyl-S-(2-hydroxy-3-chloropropyl)cysteine, 1,3-(2-propanol)-bis-S-(N-acetylcysteine), N-acetyl-S-(2-hydroxy-2-carboxyethyl)cysteine, 2,3-dichloropropionic acid, 2-chloroethanol, ethylene glycol and oxalic acid by comparison to spectra of authentic standards. No unchanged TCP was detected. From the results obtained it is concluded that metabolism of TCP by cytochromes P450 and by glutathione conjugation can result in the formation of reactive metabolites of TCP which may be responsible for TCP genotoxicity.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectDissertations, Academicen_US
dc.subjectGenetic toxicologyen_US
dc.subjectToxicology.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.contributor.advisorSipes, I. Glennen_US
dc.contributor.committeememberGandolfi, A. Jayen_US
dc.contributor.committeememberLiebler, Daniel C.en_US
dc.contributor.committeememberLaird, Hugh E.en_US
dc.contributor.committeememberCarter, Dean E.en_US
dc.identifier.proquest9127711en_US
dc.identifier.oclc710835611en_US
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