Biochemical and Biophysical Research Communications
3′-UTR polymorphism in the human CYP2A6 gene affects mRNA stability and enzyme expression☆
Section snippets
Material and methods
Subjects. Genomic DNAs and total mRNAs were extracted from 46 human liver samples obtained from Swedish kidney donors as described before [17]. Liver microsomes were prepared from 29 samples among the Swedish donors. 102 Turkish genomic DNA samples were collected from healthy individuals for pharmacogenetic studies at the Department of Biochemistry, Faculty of Pharmacy, University of Istanbul [9]. The Ethics Committee at the Karolinska Institutet approved the use of the human samples for the
Interindividual variation in hepatic CYP2A6 expression and activity
The protein level and the catalytic activity of CYP2A6 were determined in human liver samples and compared to previous data on the mRNA level in the same livers [18]. The association between the gene expression and catalytic activity of CYP2A6 and the influence of the CYP2A6*1B allele are shown in Fig. 2. The mRNA level, protein level as well as the catalytic activity of CYP2A6 measured by the formation of 7-hydroxycoumarin from coumarin were all in accordance with each other. The CYP2A6
Discussion
The results obtained indicate that the 3′-UTR plays an important role in regulation of CYP2A6 gene expression. This observation was supported by analysis of CYP2A6 genotype and phenotype in different liver samples as well as by results from both in vivo and in vitro transfection experiments using reporter constructs containing variant CYP2A6 3′-UTRs.
The CYP2A6*1B allele carries a gene conversion with the CYP2A7 gene in the 3′-UTR [3], [21]. Several studies on healthy volunteers indicated that
Acknowledgments
This study was supported by grants from The Swedish Cancer Foundation, The Swedish Research Council and by NIH (NIGMS 1-R01 GM60548).
References (34)
- et al.
CYP2A6: a human coumarin 7-hydroxylase
Toxicology
(2000) - et al.
Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism
FEBS Lett.
(1999) - et al.
Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population
FEBS Lett.
(1999) - et al.
Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity
Biochem. Biophys. Res. Commun.
(2001) - et al.
Identification of a 43-kDa protein in human liver cytosol that binds to the 3′-untranslated region of CYP2A6 mRNA
Biochem. Pharmacol.
(2001) - et al.
Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5′-upstream regulatory region
Biochem. Biophys. Res. Commun.
(1999) - et al.
Regulation of mRNA stability in mammalian cells
Gene
(2001) Diversity in translational regulation
Curr. Opin. Cell Biol.
(2001)- et al.
Regulated release of L13a from the 60S ribosomal subunit as a mechanism of transcript-specific translational control
Cell
(2003) - et al.
Interplay between hnRNP A1 and a cis-acting element in the 3′ UTR of CYP2A5 mRNA is central for high expression of the gene
FEBS Lett.
(2003)
Cell type-specific expression of hnRNP proteins
Exp. Cell Res.
Genetic polymorphism of CYP2A6 as one of the potential determinants of tobacco-related cancer risk
Biochem. Biophys. Res. Commun.
Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: implications for interindividual differences in nicotine metabolism
Drug Metab. Dispos.
Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13, the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK
Cancer Res.
A new CYP2A6 gene deletion responsible for the in vivo polymorphic metabolism of (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride in humans
J. Pharmacol. Exp. Ther.
Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking
Mol. Pharmacol.
Characterization of a novel CYP2A7/CYP2A6 hybrid allele (CYP2A6*12) that causes reduced CYP2A6 activity
Hum. Mutat.
Cited by (88)
Enzyme Regulation
2018, Comprehensive Toxicology: Third EditionCharacterization of CYP2B6 and CYP2A6 Pharmacogenetic Variation in Sub-Saharan African Populations
2024, Clinical Pharmacology and TherapeuticsNatural polymorphisms in ZmIRX15A affect water-use efficiency by modulating stomatal density in maize
2023, Plant Biotechnology JournalPseudogenes in Cancer: State of the Art
2023, CancersAn in-silico analysis to identify structural, functional and regulatory role of SNPs in hMRE11
2023, Journal of Biomolecular Structure and Dynamics
- ☆
Abbreviations: 3′-UTR, 3′-untranslated region; SNP, single nucleotide polymorphism; NNK, methylnitrosamino-1-(3-pyridyl)-1-butanone; NDEA, N-nitrosodiethylamine; ActD, actinomycin D.