Linked Life Data

9548799

Source:http://linkedlifedata.com/resource/pubmed/id/9548799

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
1998-7-9
pubmed:abstractText
Acetaminophen (APAP), a widely used analgesic and antipyretic agent, is bioactivated by cytochromes P450 to cause severe hepatotoxicity. APAP is oxidized by two pathways to form a toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI), and a nontoxic catechol metabolite, 3-hydroxy-APAP (3-OH-APAP). We investigated the role of P450 2E1 and 2A6 in APAP oxidation by using baculovirus-expressed and highly purified forms of human P450 2E1 and 2A6. An electrochemical HPLC assay was developed to quantify both oxidative metabolites simultaneously. For the first time, it was demonstrated that human P450 2E1 selectively oxidized APAP to NAPQI (assayed as its glutathione conjugate, GS-APAP), whereas human P450 2A6 selectively oxidized APAP to 3-OH-APAP. At 1 mM APAP, the relative ratio for the formation of GS-APAP vs 3-OH-APAP with human P450 2E1 was approximately 6:1, whereas the ratio with human P450 2A6 was 1:3. Apparent Km and Vmax values for the formation of GS-APAP by human P450 2E1 were 1.3 mM and 6.9 nmol/min/nmol of P450, respectively, whereas they were 4.6 mM and 7.9 nmol/min/nmol of P450 for P450 2A6. Apparent Km and Vmax values for the formation of 3-OH-APAP by human P450 2E1 were 4.0 mM and 2.5 nmol/min/nmol of P450, respectively, whereas they were 2.2 mM and 14.2 nmol/min/nmol of P450, respectively, for P450 2A6. Thus, although at toxic doses of APAP P450 2E1 is the more efficient catalyst for the formation of the toxic metabolite NAPQI, P450 2A6 also can contribute significantly to NAPQI production.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0893-228X
pubmed:author
pubmed:issnType
Print
pubmed:volume
11
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
295-301
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1998
pubmed:articleTitle
Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and 2A6.
pubmed:affiliation
Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195, USA.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S.