Linked Life Data

18936109

Source:http://linkedlifedata.com/resource/pubmed/id/18936109

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2008-12-24
pubmed:abstractText
1-Aminobenzotriazole (1-ABT) is generally considered to be a nonselective mechanism-based inactivator of both human and non-human cytochrome P450 (P450) enzymes. Thus, 1-ABT is routinely used when conducting in vitro reaction phenotyping studies with new chemical entities in drug discovery to decipher P450 from non-P450-mediated metabolism. Experiments with pooled human liver microsomes (HLMs) demonstrated that carbon monoxide binding, although substantially reduced after a 30-min preincubation with 1-ABT, was still measurable. Thus, remaining activity of nine major human P450s (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) in HLMs was determined using established selective probe substrates after 30-min preincubation with either 1-ABT (1 mM), a positive control time-dependent inhibitor, or a competitive inhibitor. Whereas P450 2A6 and 3A4 activity was essentially eliminated upon 30-min pretreatment with 1-ABT, the other human P450s were less affected, with at least 20% activity remaining after pretreatment. In contrast, most of the known P450 selective time-dependent inhibitors were more effective inactivators than 1-ABT at lower concentrations. A particularly interesting finding was that 1-ABT was quite ineffective at inactivating P450 2C9, with roughly 60% activity remaining after pretreatment, which suggests that 1-ABT is much less selective for certain human P450s. This collection of data clearly demonstrates that assuming 1-ABT is a nonselective P450 inhibitor in vitro is risky, and false conclusions regarding remaining metabolic activity being non-P450 mediated after 1-ABT pretreatment may be made.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1521-009X
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
37
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
10-3
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator?
pubmed:affiliation
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, St. Louis Laboratories, St. Louis, Missouri, USA.
pubmed:publicationType
Journal Article