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Comparison of the Function and Expression of CYP26A1 and CYP26B1, the two Retinoic Acid Hydroxylases
- Publication Year :
- 2011
-
Abstract
- All-trans -retinoic acid ( at RA) is an important signaling molecule in all chordates. The cytochrome P450 enzymes CYP26 are believed to partially regulate cellular concentrations of at RA via oxidative metabolism and hence affect retinoid homeostasis and signaling. CYP26A1 and CYP26B1 are at RA hydroxylases that catalyze formation of similar metabolites in cell systems. However, they have only 40% sequence similarity suggesting differences between the two enzymes. The aim of this study was to determine whether CYP26A1 and CYP26B1 have similar catalytic activity, form different metabolites from at RA and are expressed in different tissues in adults. The mRNA expression of CYP26A1 and CYP26B1 correlated between human tissues except for human cerebellum in which CYP26B1 was the predominant CYP26 and liver in which CYP26A1 dominated. Quantification of CYP26A1 and CYP26B1 protein in human tissues was in agreement with the mRNA expression and showed correlation between the two isoforms. Qualitatively, recombinant CYP26A1 and CYP26B1 formed the same primary and sequential metabolites from at RA. Quantitatively, CYP26B1 had a lower K m (19 nM) and V max (0.8 pmol/min/pmol) than CYP26A1 ( K m = 50 nM and V max = 10 pmol/min/pmol) for formation of 4-OH-RA. The major at RA metabolites 4-OH-RA, 18-OH-RA and 4-oxo-RA were all substrates of CYP26A1 and CYP26B1, and CYP26A1 had a 2–10-fold higher catalytic activity towards all substrates tested. This study shows that CYP26A1 and CYP26B1 are qualitatively similar RA hydroxylases with overlapping expression profiles. CYP26A1 has higher catalytic activity than CYP26B1 and seems to be responsible for metabolism of at RA in tissues that function as a barrier for at RA exposure.
- Subjects :
- Gene isoform
Adult
Male
medicine.drug_class
Retinoic acid
Tretinoin
Biology
Spodoptera
Biochemistry
Article
Gene Expression Regulation, Enzymologic
Cell Line
Mixed Function Oxygenases
chemistry.chemical_compound
CYP26A1
Cytochrome P-450 Enzyme System
Catalytic Domain
medicine
Animals
Humans
Retinoid
Aged
Pharmacology
chemistry.chemical_classification
Cytochrome P450
Metabolism
Middle Aged
Retinoic Acid 4-Hydroxylase
Recombinant Proteins
Rats
Enzyme
chemistry
embryonic structures
biology.protein
Female
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....d75b4625c4e3d8728cac3bf91a56cdf7