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• W3097807633 endingPage "152628" @default.
• W3097807633 startingPage "152628" @default.
• W3097807633 abstract "The mechanism of clozapine-associated cardiotoxicity has not been elucidated. The formation of a reactive nitrenium ion from the drug has been suggested as the cause, however, the reason why the heart is a target remains unknown. The heart is one of the most perfused organs; therefore, it contains a large number of mitochondria per cell; these organelles are responsible for both oxygen metabolism and energy production due to high energy expenditure. Given that mitochondria play critical roles in cellular homeostasis and maintenance, this study tested the hypothesis that cardiac mitochondria are both a target and initiator of clozapine-induced cardiotoxicity through activating the drug. We investigated whether murine heart receives a relatively high amount of systemically administered drug (20 mg/kg, i.p., Wistar albino rats) and whether cardiac mice (Swiss albino) and rat (Wistar albino) mitochondria locally activate clozapine (100 μM) to a reactive metabolite. We observed a relatively large distribution of clozapine to heart tissue as well as the formation of reactive metabolites by cardiac mitochondria in situ. Mitochondrial cytochrome P450 enzymes (CYP) in cardiac tissue responsible for biotransformation of clozapine were also characterized. CYP3A4 has been found to be the major enzyme catalyzes CLZ bioactivation, while CYP1A largely and CYP3A4 partially catalyzes the formation of stable metabolites of CLZ. At 100 μM concentration, clozapine caused a significant decline in mitochondrial oxygen consumption rate in vitro as much as positive control (antimycin A), while it did not induce mitochondrial permeability transition pore opening. These data provide an explanation as to why the heart is a target for clozapine adverse effects." @default.
• W3097807633 created "2020-11-09" @default.
• W3097807633 creator A5003157478 @default.
• W3097807633 creator A5029175386 @default.
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• W3097807633 date "2021-01-01" @default.
• W3097807633 modified "2023-09-25" @default.
• W3097807633 title "Bioactivation of clozapine by mitochondria of the murine heart: Possible cause of cardiotoxicity" @default.
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• W3097807633 doi "https://doi.org/10.1016/j.tox.2020.152628" @default.
• W3097807633 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33166605" @default.
• W3097807633 hasPublicationYear "2021" @default.
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