Disease relevance of CYP26A1

• METHODS: A PCR-single strand conformation polymorphism (PCR-SSCP) strategy was developed to screen for CYP26A1 sequence variations that could affect the enzyme expression and/or activity and applied to DNA samples from 80 unrelated Caucasians, comprising 40 French healthy volunteers and 40 Italian patients with spina bifida [1].
• The recently identified retinoic acid (RA)-metabolizing cytochrome P450RAI-1 (CYP26A1) has been implicated in accelerated metabolism and rapid clearance of all-trans-retinoic acid (ATRA) during prolonged oral administration in patients with acute promyelocytic leukemia (APL), leading to a progressive decline in plasma drug levels [2].
• The effect of cellular retinoic acid binding protein-I expression on the CYP26-mediated catabolism of all-trans retinoic acid and cell proliferation in head and neck squamous cell carcinoma [3].
• While investigating the above finding, we found that expression of CYP26A1, a major retinoic acid catabolic enzyme, was up-regulated in Apc(MIN) mouse adenomas, human FAP adenomas, human sporadic colon carcinomas, and in the intestine of apc(mcr) mutant zebrafish embryos [4].
• In retinoid-sensitive neuroblastoma, lung and breast cancer cell lines, direct inhibition of retinoid-induced RARbeta2 expression blocked induction of only one of eight retinoid target genes (CYP26A1) [5].

High impact information on CYP26A1

• We provide genetic evidence that ALDH1A2 and CYP26A1 activities concurrently establish local embryonic retinoic acid levels that must be finely tuned to allow posterior organ development and to prevent spina bifida [6].
• Cyp26a1(-/-) mouse fetuses have lethal morphogenetic phenotypes mimicking those generated by excess retinoic acid administration, indicating that human CYP26A1 may be essential in controlling retinoic acid levels during development [6].
• Cyp26 enzymes generate the retinoic acid response pattern necessary for hindbrain development [7].
• Here, we show that the cytochrome p450 enzymes of the Cyp26 class, which metabolize RA into polar derivatives, function redundantly to shape RA-dependent gene-expression domains during hindbrain development [7].
• Furthermore, we show that Cyp26 enzymes are essential for exogenous RA to rescue hindbrain patterning in RA-depleted embryos [7].

Chemical compound and disease context of CYP26A1

• Evidence for a functional genetic polymorphism of the human retinoic acid-metabolizing enzyme CYP26A1, an enzyme that may be involved in spina bifida [1].
• Identification of the fenretinide metabolite 4-oxo-fenretinide present in human plasma and formed in human ovarian carcinoma cells through induction of cytochrome P450 26A1 [8].
• Strong RA induction of the RA hydroxylase P450RAI (CYP26) was confined to ERalpha-positive T47D and MCF-7 breast cancer cells and did not appear to explain the lack of detectable RA levels in these cells since RA remained undetectable when the cells were treated with 5-10 microM liarozole, a P450RAI inhibitor [9].
• Like RA, the title compound: 1) inhibited vaginal keratinization in estrogen-stimulated rats; 2) induced epidermal hyperplasia in mouse ear skin; 3) transformed mouse tail epidermis from a para- to an orthokeratotic skin type; and 4) up-regulated the CYP26 mRNA expression in rat liver [10].

Biological context of CYP26A1

• Overexpression of CYP26A1 and retinoic acid receptors (RARs) in A2780 cells were obtained by cDNAs transfection [8].
• The importance of the CYP26A1 P450 in mouse and zebrafish development flags the CYP26B1 gene as a potential developmental gene [11].
• Further active site optimisation of the CYP26A1 model built using the CYP3A4 template was performed by molecular dynamics to generate a final CYP26A1 model [12].
• In the MCF-7 CYP26A1 cell assay, the 2-(4-hydroxybenzyl)-6-methoxytetralone 5 and unsaturated benzylidene precursor 6 were found to be the most potent (IC50 = 7 and 5 microM, respectively), which was comparable with liarozole (7 microM) but considerably less active than R115866 (IC50 = 5 nM) [13].
• P450RAI (CYP26A1) maps to human chromosome 10q23-q24 and mouse chromosome 19C2-3 [14].

Anatomical context of CYP26A1

• We studied induction and regulation of CYP26A1 expression and ATRA metabolism in human intestinal (Caco-2), liver (HepG2), endothelial (HUVEC), and APL (NB4) cell lines [2].
• In endothelial cells, however, a higher concentration of ATRA (10 microM) was required to induce expression of CYP26A1 [2].
• We also show that hP450RAI mRNA expression is highly induced by RA in certain human tumor cell lines and further show that RA-inducible RA metabolism may correlate with P450RAI expression [15].
• CYP26 mRNA is up-regulated during the retinoic acid (RA)-induced neural differentiation of mouse embryonic stem cells in vitro and is transiently expressed by embryonic stem cells undergoing predominantly non-neural differentiation [16].
• Retinoic acid receptors regulate expression of retinoic acid 4-hydroxylase that specifically inactivates all-trans retinoic acid in human keratinocyte HaCaT cells [17].

Associations of CYP26A1 with chemical compounds

• Throughout development CYP26A1 degrades RA in a horizontal region that extends across the retina, but during later embryonic and postnatal retina maturation this function is reinforced by another enzyme, CYP26C1 [18].
• The potent inhibitory activity of novel 2-benzyltetralone and 2-benzylidenetetralone derivatives vs liver microsomal retinoic acid metabolizing enzymes and a MCF-7 CYP26A1 cell assay is described [13].
• Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1 [19].
• Other retinoids (retinol, 9-cis-RA, and 13-cis-RA) also induced significant CYP26A1 expression in HepG2 and NB4 cells [2].
• Specifically, CYP26C1 can also recognize and metabolize 9-cis-RA and is much less sensitive than the other CYP26 family members to the inhibitory effects of ketoconazole [20].

Regulatory relationships of CYP26A1

• Because CYP26A1 expression could not be induced by RAR ligands alone, NB4 cells were then co-treated with the RXR agonist BMS649 [21].

Other interactions of CYP26A1

• Transiently transfected cells expressing CYP26C1 convert atRA to polar water-soluble metabolites similar to those generated by CYP26A1 and -B1 [20].
• We have previously identified two cytochrome P450s, P450RAI-1 and P450RAI-2 (herein named CYP26A1 and CYP26B1), which were shown to be responsible for catabolism of atRA both in the embryo and the adult [20].
• Elevated levels of CYP26A1 protein and metabolism of 4-HPR to 4-oxo-4-HPR were found in A2780 cells transfected with RARbeta and to a lesser extent in those transfected with RARgamma [8].
• In A2780/HPR cells continuously treated with 4-HPR and producing 4-oxo-4-HPR, CYP26A1 and CRBP-I were markedly up-regulated compared with A2780 untreated cells [8].
• cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450 [15].

Analytical, diagnostic and therapeutic context of CYP26A1

• Our data suggest that upregulation of CYP26A1 expression in intestinal, endothelial, liver, and APL cells and metabolism of ATRA may play a role in rapid clearance of ATRA after continuous oral administration [2].
• In this report, we describe the identification, molecular cloning, and substrate characterization of a third member of the CYP26 family, named CYP26C1 [20].
• PCR amplifications with two sets of degenerate primers that were targeted to CYP26-specific regions were performed with cDNAs from human fetal liver and brain as templates [22].
• A Northern blot containing poly(A+)RNAs from 43 human adult and 7 human fetal tissues was tested for CYP26 expression [22].
• In a model of chronic vitamin A ingestion during aging, CYP26 mRNA expression, determined by Northern blot and RT-PCR analysis, increased progressively with dietary vitamin A (P<0.0001; marginal < control < supplemented) and age (P<0.003) [23].

References