PYRAZOLE, INTERACTIONS AND METABOLISM BY HEPATIC MICROSOMES (ALCOHOL, CYTOCHROME P450).
Item
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Title
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PYRAZOLE, INTERACTIONS AND METABOLISM BY HEPATIC MICROSOMES (ALCOHOL, CYTOCHROME P450).
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Identifier
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AAI8629686
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identifier
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8629686
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Creator
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FEIERMAN, DENNIS ELCHANON.
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Contributor
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Athur I. Cederbaum
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Date
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1986
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Language
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English
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Publisher
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City University of New York.
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Subject
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Chemistry, Biochemistry
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Abstract
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There is current interest in the interactions of alcohol and drugs. Drugs are metabolized via the liver microsomal mixed function oxidase system, which depends on cytochrome P-450 isozymes. Different populations of cytochrome P-450 isozymes can be induced via drugs, diet and alcohol. Alcohol induces a specific isozyme which plays a role in drug-alcohol interactions. This isozyme has been difficult to purify and its induction requires long term feeding of alcohol which also causes many other metabolic derangements. Hence there is a need for other models which can induce the alcohol cytochrome P-450. The goal of this research is to demonstrate that pyrazole and 4-methylpyrazole, potent inhibitors of alcohol dehydrogenase that are widely used in alcohol research, interact and induce an alcohol preferring cytochrome P-450 and moreover, these agents are metabolized by this P-450.;Pyrazole and 4-methylpyrazole treatment appear to result in the induction of an alcohol-preferring cytochrome P-450 as reflected by alcohol and drug oxidation data and binding spectra with several substrates. Pyrazole treatment does not change the content of cytochrome P-450 or the activity of the cytochrome P-450 reductase. By contrast, treatment with 4-methylpyrazole increases the content of cytochrome P-450 about two-fold. Microsomes isolated from these treated rats exhibit several properties which are similar to microsomes isolated from rats chronically fed ethanol. This suggests the possibility that pyrazole- or 4-methylpyrazole-treatment may serve as good models to study the effects that ethanol has on the hepatic mixed-function oxidase system. Pyrazole and 4-methylpyrazole can inhibit microsomal oxidation of ethanol in vitro, and the effectiveness of these agent as inhibitors is increased in microsomes isolated from rats treated with pyrazole, 4-methylpyrazole or ethanol. Furthermore, pyrazole is metabolized by microsomes in a cytochrome P-450 dependent manner and its metabolism is increased by pyrazole-, 4-methylpyrazole or ethanol-treatment. In view of the above, extreme caution would be required in the use of pyrazole or 4-methylpyrazole to assess the role of alcohol dehydrogenase dependent and independent (e.g., microsomal) pathways in contributing towards overall metabolism of ethanol, especially in induced animals.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
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Program
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Biomedical Sciences
