GENOTOXICITY OF THE PYRROLIZIDINE ALKALOIDS: ASSOCIATION WITH ADVERSE HEPATIC EFFECTS (ALKALINE ELUTION, CHEMICAL CARCINOGENESIS, ANTIMITOTIC EFFECTS).

Persistent Link:
http://hdl.handle.net/10150/187838
Title:
GENOTOXICITY OF THE PYRROLIZIDINE ALKALOIDS: ASSOCIATION WITH ADVERSE HEPATIC EFFECTS (ALKALINE ELUTION, CHEMICAL CARCINOGENESIS, ANTIMITOTIC EFFECTS).
Author:
PETRY, THOMAS WILLIAM.
Issue Date:
1984
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:
Pyrrolizidine alkaloids (PAs) produce a variety adverse hepatic effects, including acute toxicity, carcinogenicity and potent, persistent antimitotic effects. Additionally several have been evaluated as antineoplastic agents. PAs constitute significant health hazards to man and domestic animals. The mechanism(s) by which PAs induce these effects are not known. These studies were designed to test the hypothesis that some or all of the adverse hepatic effects and possibly the antineoplastic activity of PAs associate with or are mediated by a genotoxic interaction with cellular DNA. The first objective of the studies was to verify the in vivo gentoxicity of the PAs, in the process characterizing the type(s) of DNA damage induced. Hepatic DNA damage induced by the model PA monocrotaline (MCT) was assessed following i.p. administration to adult male Sprague-Dawley rats. DNA damage was characterized by the alkaline elution technique. MCT was found to induce both DNA-DNA interstrand and DNA-protein cross-links. No evidence was seen for the induction of DNA single-strand breaks, although the presence of small numbers of DNA single-strand breaks could have been masked by the overwhelming predominance of DNA cross-links. DNA-DNA interstrand cross-linking reached a maximum within 12 hr and thereafter decreased over a protracted period. By 96 hr post administration, the calculated cross-linking factor was no longer statistically different from zero (control). Further studies were performed to test the effects of agents known to modulate the formation/disposition of the proposed reactive intermediate and the toxic effects of the PAs. Consistent with its involvement in the mechanism of the toxicity of the PAs, genotoxicity was shown to modulate in the same direction and to similar degree as does the toxicity. Other PAs, or derivatives thereof, were evaluated in addition to MCT. Structural requirements for DNA cross-linking potential were shown to be similar to those required for the induction of toxic and antimitotic effects, again consistent with the involvement of DNA cross-linking in the mechanism of these effects. Indicine N-oxide however, an experimental antineoplastic agent, was shown not to mediate its cytotoxic effects via this mechanism.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Alkaloids -- Toxicology.; Genetic toxicology.
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.titleGENOTOXICITY OF THE PYRROLIZIDINE ALKALOIDS: ASSOCIATION WITH ADVERSE HEPATIC EFFECTS (ALKALINE ELUTION, CHEMICAL CARCINOGENESIS, ANTIMITOTIC EFFECTS).en_US
dc.creatorPETRY, THOMAS WILLIAM.en_US
dc.contributor.authorPETRY, THOMAS WILLIAM.en_US
dc.date.issued1984en_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.abstractPyrrolizidine alkaloids (PAs) produce a variety adverse hepatic effects, including acute toxicity, carcinogenicity and potent, persistent antimitotic effects. Additionally several have been evaluated as antineoplastic agents. PAs constitute significant health hazards to man and domestic animals. The mechanism(s) by which PAs induce these effects are not known. These studies were designed to test the hypothesis that some or all of the adverse hepatic effects and possibly the antineoplastic activity of PAs associate with or are mediated by a genotoxic interaction with cellular DNA. The first objective of the studies was to verify the in vivo gentoxicity of the PAs, in the process characterizing the type(s) of DNA damage induced. Hepatic DNA damage induced by the model PA monocrotaline (MCT) was assessed following i.p. administration to adult male Sprague-Dawley rats. DNA damage was characterized by the alkaline elution technique. MCT was found to induce both DNA-DNA interstrand and DNA-protein cross-links. No evidence was seen for the induction of DNA single-strand breaks, although the presence of small numbers of DNA single-strand breaks could have been masked by the overwhelming predominance of DNA cross-links. DNA-DNA interstrand cross-linking reached a maximum within 12 hr and thereafter decreased over a protracted period. By 96 hr post administration, the calculated cross-linking factor was no longer statistically different from zero (control). Further studies were performed to test the effects of agents known to modulate the formation/disposition of the proposed reactive intermediate and the toxic effects of the PAs. Consistent with its involvement in the mechanism of the toxicity of the PAs, genotoxicity was shown to modulate in the same direction and to similar degree as does the toxicity. Other PAs, or derivatives thereof, were evaluated in addition to MCT. Structural requirements for DNA cross-linking potential were shown to be similar to those required for the induction of toxic and antimitotic effects, again consistent with the involvement of DNA cross-linking in the mechanism of these effects. Indicine N-oxide however, an experimental antineoplastic agent, was shown not to mediate its cytotoxic effects via this mechanism.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectAlkaloids -- Toxicology.en_US
dc.subjectGenetic toxicology.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.proquest8504130en_US
dc.identifier.oclc693373446en_US
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