Linked Life Data

11095583

Source:http://linkedlifedata.com/resource/pubmed/id/11095583

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2001-2-2
pubmed:abstractText
Tegafur, an anticancer prodrug, is bioactivated to 5-fluorouracil (5-FU) mainly by cytochrome P450 (P450) enzymes. The conversion from tegafur into 5-FU catalyzed by human liver microsomal P450 enzymes was investigated. In fourteen cDNA-expressed human P450 enzymes having measurable activities, CYP1A2, CYP2A6, CYP2E1, and CYP3A5 were highly active in catalyzing 5-FU formation at a tegafur concentration of 100 microM. Kinetic analysis revealed that CYP1A2 had the highest V(max)/K(m) value and that the V(max) value of CYP2A6 was high in 5-FU formation. In human liver microsomes, the activities of 5-FU formation from 10 microM, 100 microM, and 1 mM tegafur were significantly correlated with both coumarin 7-hydroxylation (r = 0.83, 0.86, and 0.74) and paclitaxel 6 alpha-hydroxylation (r = 0.77, 0.62, and 0.85) activities, respectively. Coumarin efficiently inhibited the 5-FU formation activities from 100 microM and 1 mM tegafur catalyzed by human liver microsomes that had high coumarin 7-hydroxylation activity. On the other hand, furafylline, fluvoxamine, and quercetin, as well as coumarin, showed inhibitory effects in liver microsomes that had high catalytic activities of 5-FU formation. The other P450 inhibitors examined showed weak or no inhibition in human liver microsomes. Polyclonal anti-CYP1A2 antibody, monoclonal anti-CYP2A6, and anti-CYP2C8 antibodies inhibited 5-FU formation activities to different extents in those two microsomal samples. These results suggest that CYP1A2, CYP2A6, and CYP2C8 have important roles in human liver microsomal 5-FU formation and that the involvement of these three P450 forms differs among individual humans.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Antimetabolites, Antineoplastic, http://linkedlifedata.com/resource/pubmed/chemical/Aryl Hydrocarbon Hydroxylases, http://linkedlifedata.com/resource/pubmed/chemical/CYP1A2 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/CYP2C8 protein, human, 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/Fluorouracil, http://linkedlifedata.com/resource/pubmed/chemical/Mixed Function Oxygenases, http://linkedlifedata.com/resource/pubmed/chemical/Prodrugs, http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Steroid 16-alpha-Hydroxylase, http://linkedlifedata.com/resource/pubmed/chemical/Steroid Hydroxylases, http://linkedlifedata.com/resource/pubmed/chemical/Tegafur, http://linkedlifedata.com/resource/pubmed/chemical/coumarin 7-hydroxylase
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
28
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1457-63
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2000
pubmed:articleTitle
Roles of cytochromes P450 1A2, 2A6, and 2C8 in 5-fluorouracil formation from tegafur, an anticancer prodrug, in human liver microsomes.
pubmed:affiliation
Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't