The discovery of new coding alleles of human CYP26A1 that are potentially defective in the metabolism of all-trans retinoic acid and their assessment in a recombinant cDNA expression system.
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Lee SJ, Perera L, Coulter SJ, Mohrenweiser HW, Jetten A, Goldstein JA
The discovery of new coding alleles of human CYP26A1 that are potentially defective in the metabolism of all-trans retinoic acid and their assessment in a recombinant cDNA expression system.
Pharmacogenet Genomics. 2007 Mar;17(3):169-80. doi: 10.1097/FPC.0b013e32801152d6.
- PubMed ID
- 17460545 [ View in PubMed]
- Abstract
OBJECTIVES: Retinoic acid (RA) is a critical regulator of gene expression during embryonic development and in the maintenance of adult epithelial tissues. This study was undertaken to identify genetic polymorphisms of CYP26A1 which might affect these processes. We sequenced CYP26A1 in racially diverse individuals and assessed the metabolism of retinoic acid by newly identified coding alleles of CYP26A1 in a recombinant system. METHODS: CYP26A1 was sequenced in 24 Caucasians, 24 African-Americans, 24 Asians, and 20 individuals of unknown racial origin. cDNA constructs for wild-type and coding alleles of CYP26A1 were constructed in a pcDNA3.1 expression vector and expressed in Cos-1 cells. A FLAG tag at the C-terminal end of the cDNA was used to quantitate the recombinant CYP26A1 proteins. RESULTS: A total of 13 single nucleotide polymorphisms (SNPs) were identified in CYP26A1. Three SNPs produced coding changes: R173S, F186L, and C358R. These alleles were termed as CYP26A1*2, CYP26A1*3, and CYP26A1*4, respectively, by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee at http://www.cypalleles.ki.se/. Wild type CYP26A1 protein metabolized all-trans-retinoic acid (at-RA) to 4-oxo-RA, 4-OH-RA as well as water-soluble metabolites. CYP26A1.3 (F186L) and CYP26A1.4 (C358R) allelic proteins exhibited significantly lower metabolism (40-80%) of at-RA than wild-type CYP26A1.1 protein. CONCLUSION: This is the first study to identify coding alleles of CYP26A1. Two coding alleles, CYP26A1*3 and CYP26A1*4, are predicted to be defective based on the metabolism of at-RA by the recombinant proteins. These studies suggest the need for future clinical studies of polymorphisms of CYP26A1 in embryonic development.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Tretinoin Cytochrome P450 26A1 Protein Humans UnknownSubstrateDetails - Drug Reactions
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