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    The hepatic microsomal cocaine binding protein and cocaine toxicity

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    Author
    Mahran, Laila G.
    Advisor
    El-Defrawi, Mohyee
    Date
    1992
    Type
    dissertation
    
    Metadata
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    Abstract
    ({dollar}\sp3{dollar}H) cocaine binds reversibly and with high affinity to a cocaine acceptor in microsomes of rat livers and isolated hepatocytes. Binding was studied using a filtration assay. The acceptor varied among different animal species in density and affinity for cocaine. In the rat, a cocaine tolerant animal, its density was {dollar}>{dollar}100 pmol/mg protein and Kd of 2-3 nM; while in the mouse it was 2 pmol/mg protein and Kd of 100-200 nM. The binding parameters of ({dollar}\sp3{dollar}H) cocaine to human liver microsomes were similar to those of the mouse. The cocaine acceptor was solubilized by CHAPS while retaining its high affinity for ({dollar}\sp3{dollar}H) cocaine. It behaved as an aggregate when chromatographed on Sephadex G-100 and Sepharose 6B, but SDS-PAGE analysis revealed the presence of peptides smaller than 100 KDa. Immune sera from rabbits, immunized with the soluble acceptor protein, inhibited binding of ({dollar}\sp3{dollar}H) cocaine to rat liver microsomes. Cocaine was metabolized rapidly in vivo and in hepatocytes, but little by the microsomal fraction. Cocaine at mM concentrations induced leakage of LDH and reduction of GSH levels from isolated rat hepatocytes. However, these tests could not detect hepatotoxicity at lower, more physiologically relevant, cocaine concentrations. The binding of ({dollar}\sp3{dollar}H) cocaine to its acceptor may also be a sensitive monitor of lead exposure. Even though 100 {dollar}\mu{dollar}M lead did not inhibit ({dollar}\sp3{dollar}H) cocaine binding, chronic in vivo exposure of rats to 25 ppm lead resulted in significant losses in cocaine binding. This may be due to effects on the acceptor's gene expression and can be an indicator of exposure to lead. In vivo administration of a single dose of cocaine caused significant reduction in ({dollar}\sp3{dollar}H) cocaine binding. Chronic cocaine resulted in further reductions, while withdrawal of cocaine produced recovery of the binding to its control levels. It is suggested that the reduced binding of ({dollar}\sp3{dollar}H) cocaine may result from the irreversible cocaine binding to liver microsomes that others have observed. The hepatic cocaine acceptor differed from the cocaine receptor of the brain, biochemically as well as pharmacologically. However, this acceptor may affect cocaine's central and cardiovascular actions by affecting the concentrations of free cocaine in circulation.
    Description
    University of Maryland, Baltimore. Toxicology. Ph.D. 1992
    Keyword
    Health Sciences, Toxicology
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/2512
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    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

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