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Transcriptional Regulation of CYP2C9 Gene
Open accessAbstract
Although cytochrome P450 2C9 (CYP2C9) is a major CYP expressed in the adult human liver, its mechanism of regulation is poorly known. In previous work, we have shown that CYP2C9 is inducible in primary human hepatocytes by xenobiotics including dexamethasone, rifampicin, and phenobarbital. The aim of this work was to investigate the molecular mechanism(s) controlling the inducible expression of CYP2C9. Deletional analysis of CYP2C9 regulatory region (+21 to -2088) in the presence of various hormone nuclear receptors suggested the presence of two functional response elements, a glucocorticoid receptor-responsive element (-1648/-1684) and a constitutive androstane receptor-responsive element (CAR, -1783/-1856). Each of these were characterized by co-transfection experiments, directed mutagenesis, gel shift assays, and response to specific antagonists RU486 and androstanol. By these experiments we located a glucocorticoid-responsive element imperfect palindrome at -1662/-1676, and a DR4 motif at -1803/-1818 recognized and transactivated by human glucocorticoid receptor and by hCAR and pregnane X receptor, respectively. Identification of these functional elements provides rational mechanistic basis for CYP2C9 induction by dexamethasone (submicromolar concentrations), and by phenobarbital and rifampicin, respectively. CYP2C9 appears therefore to be a primary glucocorticoid-responsive gene, which in addition, may be induced by xenobiotics through CAR/pregnane X receptor activation.
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Cited by
Godoy, P., Hewitt, N. J., Albrecht, U., Andersen, M. E., Ansari, N., Bhattacharya, S., Bode, J. G., Bolleyn, J., Borner, C., Böttger, J., et al. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1078-5 · Cited by 1,280
Hewitt, N. J., Gómez Lechón, M. J., Houston, J. B., Hallifax, D., Brown, H. S., Maurel, P., Kenna, J. G., Gustavsson, L., Lohmann, C., Skonberg, C., et al. (2007) · Drug Metabolism Reviews · doi:10.1080/03602530601093489 · Cited by 735
Self-citationInduction of Drug Metabolism: The Role of Nuclear Receptors
Handschin, C., & Meyer, U. A. (2003) · Pharmacological Reviews · doi:10.1124/pr.55.4.2 · Cited by 470
Modulation of P-glycoprotein efflux pump: induction and activation as a therapeutic strategy
Silva, R., Vilas-Boas, V., Carmo, H., Dinis-Oliveira, R. J., Carvalho, F., de Lourdes Bastos, M., & Remião, F. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2014.11.013 · Cited by 339
Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects
di Masi, A., Marinis, E. D., Ascenzi, P., & Marino, M. (2009) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2009.04.002 · Cited by 288
Metadata
- Authors
- Gerbal-Chaloin, S., Daujat, M., Pascussi, J.-M., Pichard-Garcia, L., Vilarem, M.-J., & Maurel, P.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-01
- Volume
- 277
- Issue
- 1
- Pages
- 209-217
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1972996926
- Cited by
- 262
- References
- 0
- FWCI
- 19.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Gerbal-Chaloin, S., Daujat, M., Pascussi, J.-M., Pichard-Garcia, L., Vilarem, M.-J., & Maurel, P. (2002). Transcriptional Regulation of CYP2C9 Gene. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m107228200
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