Linked Life Data

9492386

Source:http://linkedlifedata.com/resource/pubmed/id/9492386

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1998-4-2
pubmed:abstractText
Retinoids are compounds that bind to and activate one or more retinoid receptors to elicit various physiological responses. There are two families of retinoid receptors, i.e. retinoic acid receptors (RAR) and retinoid X receptors (RXR), for which the various synthetic and naturally occurring retinoids have differing selectivities. The synthetic analogs LG100268 and LGD1069 (Targretin) are RXR-selective, whereas ALRT1550 is highly RAR-selective. Naturally occurring all-trans-retinoic acid (Tretinoin) has a degree of selectivity for RAR, whereas ALRT1057 (9-cis-retinoic acid, Panretin) is equally active at RAR and RXR (i. e. a pan-agonist). To evaluate the effects of these compounds on metabolic enzymes, male Sprague-Dawley rats received daily oral doses for 4 days, and liver microsomes were prepared on day 5. As a class, these ligands exerted profound effects on hepatic microsomal metabolic enzyme levels. Those with RAR activity decreased hepatic cytochrome P450 (CYP or P450) levels and in vitro metabolism of the compound of pretreatment, whereas those exerting predominantly RXR activity increased these parameters. A similar relationship was observed when glucuronidation was examined. Hepatic CYP2B1/2 was unaffected and CYP3A was decreased by RAR-selective ALRT1550, whereas both were induced by ligands selective for RXR. However, both RAR- and RXR-selective ligands decreased CYP1A2, whereas they induced CYP4A. Although the mechanisms underlying these effects are not known, these results suggest that RAR- and RXR-binding ligands exert distinct effects on hepatic metabolism, and they indicate the potential for drug-drug interactions, especially involving CYP3A. The nature of such interactions would depend on the RAR/RXR selectivity of the ligand and the P450 isozymes responsible for the metabolism of coadministered drugs.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
26
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
234-9
pubmed:dateRevised
2004-11-17
pubmed:meshHeading
pubmed:year
1998
pubmed:articleTitle
Effects of retinoid treatment of rats on hepatic microsomal metabolism and cytochromes P450. Correlation between retinoic acid receptor/retinoid x receptor selectivity and effects on metabolic enzymes.
pubmed:affiliation
Department of Drug Safety and Disposition, Ligand Pharmaceuticals, Inc., San Diego, CA 92121, USA.
pubmed:publicationType
Journal Article