Multiple cytochromeP-450 genes are concomitantly regulated by vitamin A under steady-state conditions and by retinoic acid during hepatic first-pass metabolism

Abstract

Vitamin A (retinol) is an essential precursor for the production of retinoic acid (RA), which in turn is a major regulator of gene expression, affecting cell differentiation throughout the body. Understanding how vitamin A nutritional status, as well as therapeutic retinoid treatment, regulates the expression of retinoid homeostatic genes is important for improvement of dietary recommendations and therapeutic strategies using retinoids. This study investigated genes central to processes of retinoid uptake and storage, release to plasma, and oxidation in the liver of rats under steady-state conditions after different exposures to dietary vitamin A (deficient, marginal, adequate, and supplemented) and acutely after administration of a therapeutic dose of all-trans-RA. Over a very wide range of dietary vitamin A, lecithin:retinol acyltransferase (LRAT) as well as multiple cytochrome P-450s (CYP26A1, CYP26B1, and CYP2C22) differed by diet and were highly correlated with one another and with vitamin A status assessed by liver retinol concentration (all correlations, P < 0.05). After acute treatment with RA, the same genes were rapidly and concomitantly induced, preceding retinoic acid receptor (RAR)β, a classical direct target of RA. CYP26A1 mRNA exhibited the greatest dynamic range (change of log 2(6) in 3 h). Moreover, CYP26A1 increased more rapidly in the liver of RA-primed rats than naive rats, evidenced by increased CYP26A1 gene expression and increased conversion of [(3)H]RA to polar metabolites. By in situ hybridization, CYP26A1 mRNA was strongly regulated within hepatocytes, closely resembling retinol-binding protein (RBP)4 in location. Overall, whether RA is produced endogenously from retinol or administered exogenously, changes in retinoid homeostatic gene expression simultaneously favor both retinol esterification and RA oxidation, with CYP26A1 exhibiting the greatest dynamic change.

Enzymology of retinoic acid biosynthesis and degradation

“…In addition to the three CYP26 enzymes, several members of other CYP families, including human CYP3A4, CYP3A5, CYP3A7, CYP1A1, CYP4A11, CYP2C8, CYP2C9, CYP2C22, CYP2C39, CYP2S1, and CYP2E1 (136)(137)(138)(139)(140)(141)(142)(143)(144)(145)(146)(147)(148)(149)(150), have been shown to catabolize atRA. While CYP2C8 is catalytically more effi cient than either CYP2C9 or CYP3A4, the overall contribution of CYP2C8 to atRA hydroxylation may not be much greater than that of CYP3A4 and CYP2C9, because the two latter enzymes are expressed at about 10-fold higher levels than CYP2C8 ( 139 ).…”

“…The mouse homolog of this enzyme, CYP2C39, also exhibits atRA 4-hydroxylase activity ( 136 ). The rat CYP2C22, an ortholog of human CYP2C8 and CYP2C9, catabolizes atRA, and its expression is induced by vitamin A and exogenous RA through a canonical RA receptor-mediated mechanism, but the expression of CYP2C22 is essentially restricted to liver ( 144,148 ). Interestingly, under normal dietary con ditions, the relative level of CYP2C22 mRNA expression exceeds that of CYP26A1 by about 100-fold ( 148 ).…”

Genetic dissection of retinoid esterification and accumulation in the liver and adipose tissue

“…The liver is very much enriched in CRBP type I (CRBPI), and adipose tissue expresses both CRBPI and CRBPIII ( 28,30,31 ). Moreover, the literature proposes that the ability to esterify retinol contributes to regulation of retinol conversion to RA ( 32,33 ). The present studies are aimed at gaining understanding of the roles of DGAT1 and its ARAT activity and CRBPI in hepatic and adipose RE synthesis, and of how RE formation may infl uence RA availability and RA-responsive gene expression.…”

DHRS3, a retinal reductase, is differentially regulated by retinoic acid and lipopolysaccharide-induced inflammation in THP-1 cells and rat liver

“…After 6 h, the rats were killed by CO 2 inhalation, blood samples were drawn for preparation of plasma, and tissues were collected and immediately snap-frozen for RNA isolation (45). Liver samples from rats that had been fed the same diet lacking vitamin A to produce a state of vitamin A deficiency were also used; the rats were then treated with a single dose of 100 g of RA in a time-course study, as described previously (32,33). Rats were euthanized, and the liver was collected at time 0 (vehicle control) and 3, 6, 10, and 16 h after RA administration.…”