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.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/282154 |
| Date | January 1996 |
| Creators | Waters, Stephen Joseph, 1957- |
| Contributors | Gandolfi, A. Jay |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | en_US |
| Detected Language | English |
| Type | text, Dissertation-Reproduction (electronic) |
| 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. |
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