Linked Life Data

18328680

Source:http://linkedlifedata.com/resource/pubmed/id/18328680

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4-5
pubmed:dateCreated
2008-4-8
pubmed:abstractText
Although regulation of phase I drug metabolism in human liver is relatively well studied, the regulation of phase II enzymes and of drug transporters is incompletely characterized. Therefore, we used human liver slices to investigate the PXR, CAR and AhR-mediated induction of drug transporters and phase I and II metabolic enzymes. Precision-cut human liver slices were incubated for 5 or 24h with prototypical inducers: phenobarbital (PB) (50 microM) for CAR, beta-naphthoflavone (BNF) (25 microM) for AhR, and rifampicin (RIF) (10 microM) for PXR, and gene expression of the phase I enzymes CYP1A1, 1A2, 3A4, 3A5, 2B6, 2A6, the phase II enzymes UGT1A1 and 1A6, and the transporters MRP2, MDR1, BSEP, NTCP and OATP8 was measured. BNF induced CYP1A1, UGT1A1 and UGT1A6 and MRP2, NTCP and MDR1. RIF induced CYP3A4, 3A5, 2B6, 2A6, UGT1A1, UGT1A6 and BSEP, MRP2 and MDR1 and slightly downregulated OATP8. PB induced CYP3A4, 3A5, 2B6 and 2A6, UGT1A1 and all transporters. Large interindividual differences were found with respect to the level of induction. Enzyme activity of CYP3A4, measured by testosterone metabolism, was increased after 24h by RIF. 7-Ethoxycoumarin O-deethylation activity, mediated predominantly by CYP 1A1/1A2 but also by other CYPs, was increased after 24h with PB. We have shown that regulation of all phases of the (in)activation of a drug via the CAR, AhR and the PXR pathways can be studied in human liver slices. The concomitant induction of metabolic enzymes and transporters shows that also in the human liver transporters and metabolic enzymes are regulated coordinately.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0928-0987
pubmed:author
pubmed:issnType
Print
pubmed:day
23
pubmed:volume
33
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
380-9
pubmed:meshHeading
pubmed:year
2008
pubmed:articleTitle
Coordinated induction of drug transporters and phase I and II metabolism in human liver slices.
pubmed:affiliation
Department of Pharmacokinetics and Drug Delivery, Groningen Research Institute for Pharmacy, University of Groningen, Ant. Deusinglaan 1, 9713 AV Groningen, The Netherlands. P.Olinga@rug.nl
pubmed:publicationType
Journal Article, In Vitro