In vivo and in vitro toxicity of M-741 (3,15 di-(5,5-dimethyl-3-N(-(cyclopropylmethylinium)-(N-propylinium));-1-cyclohex-1-enyl);-7,11,18,21-tetraoxa-3,15-diazatrispiro (5.2.2.5.2.2); heneicosane)

Persistent Link:
http://hdl.handle.net/10150/282154
Title:
In vivo and in vitro toxicity of M-741 (3,15 di-(5,5-dimethyl-3-N(-(cyclopropylmethylinium)-(N-propylinium));-1-cyclohex-1-enyl);-7,11,18,21-tetraoxa-3,15-diazatrispiro (5.2.2.5.2.2); heneicosane)
Author:
Waters, Stephen Joseph, 1957-
Issue Date:
1996
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:
M-741 (3,15 di-[5,5-dimethyl-3-N[-(cyclopropylmethylinium)-(N-propylinium]-1-cyclohex-1-enyl]-7,11,18,21-tetraoxa-3,15-diazatrispiro [5.2.2.5.2.2] heneicosane produces hepatotoxicity in rats following intravenous administration. Hepatocellular pathology is characterized by parenchymal cell necrosis and inflammatory cell infiltration. Electron microscopic evaluation could not identify any treatment-related effects on mitochondria or the production of cytoplasmic lysosomal lamellar bodies. The M-741-induced hepatotoxicity is not modified by manipulations of nutritional status (fasting), hepatic enzyme induction (phenobarbital) or interference (glutathione depletion) with potential detoxication pathways. The M-741 pharmacokinetic profile is best described by a three compartment model and displays a rapid distribution and terminal elimination. In contrast, hepatic tissue concentrations of M-741 are elevated following administration and prolonged tissue residence is observed. These data are consistent with rapid hepatic uptake and bioaccumulation of M-741. The M-741 hepatotoxicity can be modeled in precision-cut hepatic slices in dynamic culture at concentrations which are measured during in vivo toxication. The toxicophore of the M-741 is the enamino-ether quat moiety and not the spiro-diamine portion of the molecule. Structural analogs of the enamino-ether quat also produced in vitro hepatotoxicity. The in vitro toxicity of M-741 demonstrated temperature dependence and the toxicity could be initiated by short, 30 to 60 minute, pulsed exposure of the hepatic slices to M-741. These findings are consistent with rapid hepatocellular transport of M-741. Hepatic slices accumulated intracellular levels of M-741 during pulsed exposure. M-741 was transported against a concentration gradient and the transport displayed temperature dependence. Known substrates for cationic transport in hepatocytes, d-tubocurarine and triethylme thylammonium bromide, did not reduce M-741 uptake in hepatic slice competition experiments, however, the sensitivity of these measurements may have been inadequate to determine competitive effects on initial uptake velocities. Alternatively, M-741 may be transported intracellularly by absorptive endocytosis as has been demonstrated for other cationic compounds.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Pharmacology.; Health Sciences, Pharmacology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmacology and Toxicology
Degree Grantor:
University of Arizona
Advisor:
Gandolfi, A. Jay

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleIn vivo and in vitro toxicity of M-741 (3,15 di-(5,5-dimethyl-3-N(-(cyclopropylmethylinium)-(N-propylinium));-1-cyclohex-1-enyl);-7,11,18,21-tetraoxa-3,15-diazatrispiro (5.2.2.5.2.2); heneicosane)en_US
dc.creatorWaters, Stephen Joseph, 1957-en_US
dc.contributor.authorWaters, Stephen Joseph, 1957-en_US
dc.date.issued1996en_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.abstractM-741 (3,15 di-[5,5-dimethyl-3-N[-(cyclopropylmethylinium)-(N-propylinium]-1-cyclohex-1-enyl]-7,11,18,21-tetraoxa-3,15-diazatrispiro [5.2.2.5.2.2] heneicosane produces hepatotoxicity in rats following intravenous administration. Hepatocellular pathology is characterized by parenchymal cell necrosis and inflammatory cell infiltration. Electron microscopic evaluation could not identify any treatment-related effects on mitochondria or the production of cytoplasmic lysosomal lamellar bodies. The M-741-induced hepatotoxicity is not modified by manipulations of nutritional status (fasting), hepatic enzyme induction (phenobarbital) or interference (glutathione depletion) with potential detoxication pathways. The M-741 pharmacokinetic profile is best described by a three compartment model and displays a rapid distribution and terminal elimination. In contrast, hepatic tissue concentrations of M-741 are elevated following administration and prolonged tissue residence is observed. These data are consistent with rapid hepatic uptake and bioaccumulation of M-741. The M-741 hepatotoxicity can be modeled in precision-cut hepatic slices in dynamic culture at concentrations which are measured during in vivo toxication. The toxicophore of the M-741 is the enamino-ether quat moiety and not the spiro-diamine portion of the molecule. Structural analogs of the enamino-ether quat also produced in vitro hepatotoxicity. The in vitro toxicity of M-741 demonstrated temperature dependence and the toxicity could be initiated by short, 30 to 60 minute, pulsed exposure of the hepatic slices to M-741. These findings are consistent with rapid hepatocellular transport of M-741. Hepatic slices accumulated intracellular levels of M-741 during pulsed exposure. M-741 was transported against a concentration gradient and the transport displayed temperature dependence. Known substrates for cationic transport in hepatocytes, d-tubocurarine and triethylme thylammonium bromide, did not reduce M-741 uptake in hepatic slice competition experiments, however, the sensitivity of these measurements may have been inadequate to determine competitive effects on initial uptake velocities. Alternatively, M-741 may be transported intracellularly by absorptive endocytosis as has been demonstrated for other cationic compounds.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.subjectHealth Sciences, Pharmacology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmacology and Toxicologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGandolfi, A. Jayen_US
dc.identifier.proquest9713383en_US
dc.identifier.bibrecord.b34376100en_US
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