Linked Life Data

10945865

Source:http://linkedlifedata.com/resource/pubmed/id/10945865

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2000-9-12
pubmed:abstractText
We have previously shown racial differences in propranolol kinetics, with the largest differences appearing to be in its 4-hydroxylation. The purpose of this study was to identify and confirm the cytochrome P450 enzymes (CYP) with propranolol 4-hydroxylase activity, describe their enzyme kinetics, and determine whether there were racial differences in their catalytic activity. Eleven human recombinant, expressed CYPs were screened, but only CYP1A2 and CYP2D6 possessed propranolol 4-hydroxylase activity. Subsequent studies were conducted in human liver microsomes, including correlation, inhibition, enzyme kinetics, and racial comparison studies. Significant correlations were noted between propranolol 4-hydroxylation and ethoxyresorufin-O-deethylation (marker of CYP1A2 activity), with marked improvement in the correlations when CYP2D6-mediated propranolol 4-hydroxylation was inhibited with quinidine. Inhibition studies showed that quinidine inhibited approximately 55% of propranolol 4-hydroxylation and furaphylline (CYP1A2-selective inhibitor) inhibited about 45% of propranolol 4-hydroxylation. Median (range) parameter estimates of (S)-4-hydroxypropranolol [(S)-HOP] formation were a V(max) value of 307 (165-2397) and 721 (84-1975) pmol/mg of protein/60 min for CYP1A2 and CYP2D6, respectively, and a K(m) value of 21.2 (8.9-77.5) and 8.5 (5.9-31.9) microM for CYP1A2 and CYP2D6, respectively. CYP1A2- and CYP2D6-mediated propranolol 4-hydroxylation was about 70 and 100% higher (P <.05 for both), respectively, in African-Americans compared with Caucasians. In summary, we found that both CYP1A2 and CYP2D6 catalyze formation of 4-hydroxypropranolol and that both enzymes exhibited racial differences in this reaction. The observed racial differences in drug metabolism may have relevance to drug efficacy, toxicity, or carcinogen activation for CYP1A2 or CYP2D6 substrates.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
294
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1099-105
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:10945865-African Continental Ancestry Group, pubmed-meshheading:10945865-Aryl Hydrocarbon Hydroxylases, pubmed-meshheading:10945865-Cytochrome P-450 CYP1A2, pubmed-meshheading:10945865-Cytochrome P-450 CYP2D6, pubmed-meshheading:10945865-Cytochrome P-450 Enzyme System, pubmed-meshheading:10945865-Enzyme Inhibitors, pubmed-meshheading:10945865-European Continental Ancestry Group, pubmed-meshheading:10945865-Female, pubmed-meshheading:10945865-Humans, pubmed-meshheading:10945865-Hydroxylation, pubmed-meshheading:10945865-Kinetics, pubmed-meshheading:10945865-Male, pubmed-meshheading:10945865-Microsomes, Liver, pubmed-meshheading:10945865-Mixed Function Oxygenases, pubmed-meshheading:10945865-Propranolol, pubmed-meshheading:10945865-Quinidine, pubmed-meshheading:10945865-Recombinant Proteins, pubmed-meshheading:10945865-Stereoisomerism
pubmed:year
2000
pubmed:articleTitle
CYP1A2 and CYP2D6 4-hydroxylate propranolol and both reactions exhibit racial differences.
pubmed:affiliation
College of Pharmacy, University of Tennessee, Memphis, USA. Johnson@cop.ufl.edu
pubmed:publicationType
Journal Article, Comparative Study, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't