Lipopolysaccharide opposes the induction of CYP26A1 and CYP26B1 gene expression by retinoic acid in the rat liver in vivo.
Retinoic acid (RA), a principal metabolite of vitamin A (retinol), is an essential endogenous regulator of gene transcription and an important therapeutic agent. The catabolism of RA must be well regulated to maintain physiological concentrations of RA. The cytochrome P450 (CYP) gene family CYP26, which encodes RA-4-hydroxylase activity, is strongly implicated in the oxidation of RA. Inflammation alters the expression of numerous genes; however, whether inflammation affects CYP26 expression is not well understood. We investigated the regulation of CYP26A1 and CYP26B1 mRNA levels by RA and LPS in the rat liver, as the liver is centrally involved in retinoid metabolism and the acute-phase response to LPS. Both CYP26A1 and CYP26B1 mRNA were induced in <4 h by a single oral dose of all-trans-RA. RA-induced responses of both CYP26A1 and CYP26B1 were significantly attenuated in rats with LPS-induced inflammation whether LPS was given concurrently with RA or after the RA-induced increase in CYP26A1 and CYP26B1 mRNA levels. When RA and LPS were administered simultaneously (6-h study), LPS alone had little effect on either CYP26A1 or CP26B1 mRNA, but LPS reduced by 80% the RA-induced increase in CYP26A1 mRNA (P<0.02), with a similar trend for CYP26B1 mRNA. When LPS was administered 4 h after RA (16-h study), it abrogated the induction of CYP26A1 (P<0.02) and CYP26B1 (P<0.01). Overall, these results suggest that inflammation can potentially disrupt the balance of RA metabolism and maintenance of RA homeostasis, which may possibly affect the expression of other RA-regulated genes.
Zolfaghari
Reza
R
Department of Nutritional Sciences, Pennsylvania State University, S-126 Henderson Bldg. South, Univ. Park, PA 16802, USA.
Cifelli
Christopher J
CJ
Lieu
Siam O
SO
Chen
Qiuyan
Q
Li
Nan-qian
NQ
Ross
A Catharine
AC
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007527:Isoenzymes / Q000096:biosynthesis; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D011070:Poly I-C; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000072516:Retinoic Acid 4-Hydroxylase; D013997:Time Factors; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology
D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051196:Toll-Like Receptor 3; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607082:Cyp26b1 protein, rat; D000072516:Retinoic Acid 4-Hydroxylase; D011070:Poly I-C