Linked Life Data

20599501

Source:http://linkedlifedata.com/resource/pubmed/id/20599501

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2010-8-23
pubmed:abstractText
Drugs for weight loss have been in use for nearly hundred years. Orlistat (Xenical) is a non-centrally acting anti-obesity drug that inactivates gastric and intestinal lipases, thus, preventing absorption of dietary triglycerides. There are reports indicating that Orlistat reduces bioavailability of Cyclosporin to a clinically relevant degree. Since Cyclosporin is metabolized by cytochrome P450 CYP3A4, we examined whether interaction between Orlistat and Cyclosporin involves induction of CYP3A4. Human Caucasian colon adenocarcinoma cells LS174T and primary cultures of human hepatocytes were used, as in vitro models of intestinal and hepatic cells, respectively. Treatment of LS174T cells for 24h with Orlistat (1-100mg/L) did not cause induction of CYP3A4 mRNA levels as compared to control cells while Orlistat (100mg/L) slightly induced CYP3A4 mRNA in human hepatocytes. Rifampicin, a model CYP3A4 inducer, significantly induced CYP3A4 mRNA in both types of cells. The level of CYP3A4 protein in human hepatocytes was increased by Orlistat after 48h, while rifampicin strongly induced CYP3A4 protein level. In addition, Orlistat moderately dose-independently activated pregnane X receptor (PXR) in LS174T cells transiently transfected with p3A4-luc reporter construct containing the basal promoter (-362/+53) with proximal PXR response element and the distal xenobiotic responsive enhancer module (-7836/-7208) of the CYP3A4 gene 5'-flanking region. In conclusion, we report here that Orlistat is weak PXR activator and CYP3A4 inducer in human hepatocytes, but it has no effect on CYP3A4 in intestinal cells, implying no role of CYP3A4 induction in the interaction between Orlistat and Cyclosporin in absorption process.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1879-0720
pubmed:author
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
41
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
276-80
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
Investigation of Orlistat effects on PXR activation and CYP3A4 expression in primary human hepatocytes and human intestinal LS174T cells.
pubmed:affiliation
Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Slechtitelu 11, Olomouc, Czech Republic.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't