Switch to
Predicate | Object |
---|---|
rdf:type | |
lifeskim:mentions | |
pubmed:issue |
5
|
pubmed:dateCreated |
1994-3-1
|
pubmed:abstractText |
Biotransformation reactions catalyzed by human cytochrome P450 1A2 (P450 1A2) appear to play a significant role in both the metabolic clearance of drugs and the activation of environmental contaminants and drugs to toxic or carcinogenic species. Furafylline is a potent and selective inhibitor of P450 1A2 activity in human liver microsomes [Sesardic, D., Boobis, A., Murray, B., Murray, S., Segura, J., De La Torre, R., and Davies, D. (1990) Br. J. Clin. Pharmacol. 29, 651-663] which may be of great utility in defining the role of P450 1A2 in metabolic processes. We have investigated the hypothesis that furafylline is a mechanism-based inhibitor of P450 1A2. Key findings consistent with this hypothesis are the following: (1) Furafylline causes a time- and cofactor-dependent loss of P450 1A2 activity which does not return upon dialysis. (2) The loss of activity is associated with a reduction of P450 spectral content which is in turn proportional in amount to P450 1A2-associated catalytic activity in uninhibited microsomes from 7 individual livers. (3) The inactivation of P450 1A2 is characterized by a Ki of 23 microM, a kinact of 0.87 min-1 and a furafylline depletion-based partition ratio of approximately 3-6 metabolic events per inactivating event. (4) The processing of the C-8 methyl group of furaylline is involved in inactivation as demonstrated by the observation of a deuterium isotope effect of approximately 2.0 on kinact and no effect on Ki when the C-8 methyl group protons of furafylline are replaced with deuterium atoms.(ABSTRACT TRUNCATED AT 250 WORDS)
|
pubmed:grant | |
pubmed:language |
eng
|
pubmed:journal | |
pubmed:citationSubset |
IM
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 CYP1A2,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome P-450 Enzyme System,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/NADP,
http://linkedlifedata.com/resource/pubmed/chemical/Oxidoreductases,
http://linkedlifedata.com/resource/pubmed/chemical/Theophylline,
http://linkedlifedata.com/resource/pubmed/chemical/furafylline
|
pubmed:status |
MEDLINE
|
pubmed:issn |
0893-228X
|
pubmed:author | |
pubmed:issnType |
Print
|
pubmed:volume |
6
|
pubmed:owner |
NLM
|
pubmed:authorsComplete |
Y
|
pubmed:pagination |
649-56
|
pubmed:dateRevised |
2007-11-14
|
pubmed:meshHeading |
pubmed-meshheading:8292742-Biotransformation,
pubmed-meshheading:8292742-Cytochrome P-450 CYP1A2,
pubmed-meshheading:8292742-Cytochrome P-450 Enzyme System,
pubmed-meshheading:8292742-Dialysis,
pubmed-meshheading:8292742-Humans,
pubmed-meshheading:8292742-Isoenzymes,
pubmed-meshheading:8292742-Kinetics,
pubmed-meshheading:8292742-Microsomes, Liver,
pubmed-meshheading:8292742-NADP,
pubmed-meshheading:8292742-Oxidoreductases,
pubmed-meshheading:8292742-Theophylline
|
pubmed:articleTitle |
Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline.
|
pubmed:affiliation |
Department of Medicinal Chemistry, University of Washington, Seattle 98195.
|
pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, U.S. Gov't, P.H.S.
|