Suppression of the expression of the CYP2B1/2 gene by retinoic acids.
The effects of 5alpha-androsten-3alpha-ol (ASE), and retinoic acids (RAs) and their precursors on the phenobarbital (PB)-mediated induction of CYP2B1 and 2B2 were examined in cultured rat hepatocytes. Two isomers of RA, 9-cis- and all-trans-RA, suppressed markedly the effect of PB on CYP2B1/2 expression, while ASE had no suppressive effect. The effect of 9-cis-RA appeared at a lower concentration than the all-trans-isomer, indicating the dominant action of the former isomer. Suppression with 9-cis-retinal was also observed, but all-trans-retinol and -retinal were without effect. These results suggest that: (1) ASE, an inverse agonist for the constitutive androstane receptor (CAR), does not play a major role in the suppression of the CYP2B; (2) 9-cis-RA suppresses CYP2B induction by reducing ligand-free retinoid X-receptors (RXR) available for dimerization with the CAR; and (3) enzymes responsible for RA formation play an important role in the mechanism governing CYP2B regulation.
Yamada
H
H
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Yamaguchi
T
T
Oguri
K
K
D000737:Androstenols / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects*; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D015151:Immunoblotting; D007536:Isomerism; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
D000737:Androstenols; D000090702:Constitutive Androstane Receptor; D065607:Cytochrome P-450 Enzyme Inhibitors; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; C034744:androst-5-en-3-ol; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; C025619:steroid 16-beta-hydroxylase; D010634:Phenobarbital