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 (18.104.22.168.2.2); heneicosane)
AuthorWaters, Stephen Joseph
AdvisorGandolfi, A. Jay
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PublisherThe University of Arizona.
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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 [22.214.171.124.2.2] 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.
Degree ProgramGraduate College
Pharmacology and Toxicology