Linked Life Data

12695340

Source:http://linkedlifedata.com/resource/pubmed/id/12695340

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2003-4-15
pubmed:abstractText
Human CYP3A4 metabolizes a majority of clinically important substrates at variable rates. Accounting for these unpredictable rates is the wide variation noted in expression of this enzyme that is due, in part, to xenobiotic exposure. We used primary cultures of human hepatocytes from 17 individuals to assess the inducibility of CYP3A4 mRNA by prototypical inducers, dietary flavonoids, and botanicals. Those agents producing the greatest mRNA accumulation were 10 microM RIF (699 +/- 307% of control levels) 100 microM phenytoin (707 +/- 188% of control), 1 mM phenobarbital (536 +/- 207% of control), and 100 microM omeprazole (404 +/- 8% of control). Various concentrations of RIF were found to exhibit a typical dose-response curve for CYP3A4 mRNA content. A reporter gene assay using the human pregnane X receptor (hPXR) and promoter regions of CYP3A4 transiently transfected into HepG2 cells, exhibited inductive properties by the aforementioned therapeutics that were similar to those observed in hepatocytes. Several flavonoids including quercetin, resveratrol, and curcumin were also examined for their ability to induce CYP3A4 in human hepatocytes. Only quercetin produced accumulation of CYP3A4 mRNA (230 +/- 73% of control). When examined in a reporter gene assay, this flavonoid exhibited negligible increases in luciferase activity suggesting that quercetin induced CYP3A4 by mechanisms that may not involve PXR. We also examined the effects of herbals on CYP3A4 expression in human hepatocytes. Grapeseed extract, ginseng, silymarin, and kava-kava produced 270 +/- 73, 155 +/- 83, 100 +/- 10, and 386 +/- 185% of control CYP3A4 mRNA, respectively. Of these botanicals only kava-kava produced enhanced luciferase activity (11.6 +/- 2.1 fold above DMSO treated cells). Such results indicate that kava-kava required PXR to mediate CYP3A4 induction. Collectively, results demonstrated that several botancials induce CYP3A4, suggesting the potential for drug-herbal interactions.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
31
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
533-9
pubmed:dateRevised
2008-11-21
pubmed:meshHeading
pubmed-meshheading:12695340-Adolescent, pubmed-meshheading:12695340-Adult, pubmed-meshheading:12695340-Aged, pubmed-meshheading:12695340-Blotting, Northern, pubmed-meshheading:12695340-Child, pubmed-meshheading:12695340-Child, Preschool, pubmed-meshheading:12695340-Cytochrome P-450 CYP3A, pubmed-meshheading:12695340-Cytochrome P-450 Enzyme System, pubmed-meshheading:12695340-Enzyme Induction, pubmed-meshheading:12695340-Female, pubmed-meshheading:12695340-Flavonoids, pubmed-meshheading:12695340-Gene Expression Regulation, Enzymologic, pubmed-meshheading:12695340-Hepatocytes, pubmed-meshheading:12695340-Humans, pubmed-meshheading:12695340-Male, pubmed-meshheading:12695340-Middle Aged, pubmed-meshheading:12695340-Pharmaceutical Preparations, pubmed-meshheading:12695340-Pharmacology, pubmed-meshheading:12695340-Plant Extracts, pubmed-meshheading:12695340-Plant Preparations, pubmed-meshheading:12695340-RNA, Messenger
pubmed:year
2003
pubmed:articleTitle
Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products.
pubmed:affiliation
California Toxicology Research Institute, Carlsbad, California 92009, USA. jraucy@puracyp.com
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S.