Abstract
THE mammalian cytochrome P450-dependent monooxygenase system is involved in the metabolism of drugs and chemical carcinogens1–5. The role of these enzymes in toxicological response is exemplified by an autosomal recessive polymorphism at the cytochrome P450 CYP2D6 debrisoquine hydroxylase locus which results in the severely compromised metabolism of at least 25 drugs, and which in some cases can lead to life-threatening side-effects3,6–12. In addition, this polymorphism, which affects 8–10% of the caucasian population, has been associated with altered susceptibility to lung and bladder cancer13–16. Here we report the identification of the primary mutation responsible for this metabolic defect and the development of a simple DNA-based genetic assay to allow both the identification of most individuals at risk of drug side-effects and clarification of the conflicting reports on the association of this polymorphism with cancer susceptibility13–18.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nebert, D. W. in Phenotypic Variation in Populations, Relevance to Risk Assessment (eds Woodhead, A. D., Bender, M. A. & Leonard, R. C.) (Plenum, New York, 1988).
Wolf, C. R. Trends Genet. 2, 209–214 (1986).
Guengerich, F. P. (ed.) Cytochrome P450, Vols I and II (CRC, Baton Roca, 1987).
Nebert, D. W. et al. DNA 8, 1–14 (1989).
Gonzalez, F. J. Pharmac. Rev. 40, 243–287 (1989).
Eichelbaum, M., Spannbrucker, N., Steinke, B. & Dengler, H. J. Eur. J. clin. Pharmacol. 16, 183–187 (1979).
Mahgoub, A. et al. Lancet ii, 584–586 (1977).
Tucker, G. T. et al. Lancet ii, 718 (1977).
Meyer, U. A. et al. Xenobiotica 16, 449–464 (1986).
Eichelbaum, M. ISI Atlas of Science-Pharmacology 2, 243–251 (1988).
Gonzalez, F. J. et al. Nature 331, 442–446 (1988).
Forrester, L. M. & Wolf, C. R. in Metabolic Basis of Acquired Disease (eds Cohen, R. D., Alberti, K. G. M. M., Lewis, B. & Denman, A. M.) 3–18 (Balliere Tindall, London, 1990).
Ayesh, R. et al. Nature 312, 169–170 (1984).
Cuporaso, N. et al. Proc. Soc. clin. Oncol. 8, Abstract 336 (1988).
Cuporaso, N. et al. Cancer Res. 49, 3675–3679 (1989).
Kaisary, A. et al. Cancer Res. 47, 5488–5493, (1987).
Roots, L. et al. Klin. Wochenschr. 66, Suppl. XI, 87–97 (1988).
Spiers, C. J. et al. Br. J. clin. Pharmac. 29, 101–109 (1989).
Kimura, S. et al. Am. J. hum. Genet. 45, 889–904 (1989).
Skoda, R. C., Gonzalez, F. J., Demierre, A. & Meyer, U. A. Proc. natn. Acad. Sci. U.S.A. 85, 5240–5243 (1988).
Gaedigk, A., Blum, M., Meyer, U. A. & Eichelbaum, M. Naunyn-Schmiedeberg's Arch. Pharmac. 341, Suppl., R109 (1990).
Feinberg, D. P. & Vogelstein, B. Analyt. Biochem. 136, 6–13 (1983).
Kwok, S. C. M. et al. Biochemistry 24, 556–561 (1985).
Sanger, F. et al. J. molec. Biol. 143, 161–178 (1980).
Biggin, M. D., Gibson, T. J. & Hong, G. F. Proc. natn. Acad. Sci. U.S.A. 80, 3963–3965 (1983).
Staden, R. Nucleic Acids Res. 14, 217–231 (1986).
Kronbach, T. et al. Analyt. Biochem. 162, 24–32 (1987).
Saiki, R. K. et al. Science 239, 487–491 (1988).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gough, A., Miles, J., Spurr, N. et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 347, 773–776 (1990). https://doi.org/10.1038/347773a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/347773a0
This article is cited by
-
The impact of CYP2D6*4 and GSTP1 Ile105Val polymorphisms on the susceptibility to develop BCR-ABL1 negative myeloproliferative neoplasms
Molecular Biology Reports (2020)
-
The CYP2D6 VCF Translator
The Pharmacogenomics Journal (2017)
-
CYP2D6 and tamoxifen: DNA matters in breast cancer
Nature Reviews Cancer (2009)
-
Defining drug disposition determinants: a pharmacogenetic–pharmacokinetic strategy
Nature Reviews Drug Discovery (2008)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.