Skip to main content
NCBI home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1990 Dec;47(6):994–1001.

The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934----A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3' splice recognition site.

N Hanioka 1, S Kimura 1, U A Meyer 1, F J Gonzalez 1
PMCID: PMC1683916  PMID: 1978565

Abstract

The debrisoquine polymorphism is a common genetic defect that results in deficient oxidation of debrisoquine and numerous other drugs. These compounds are metabolized by a form of cytochrome P450, designated CYP2D6. Some 5%-10% of Caucasians are unable to metabolize debrisoquine, because of mutant alleles of CYP2D6. A CYP2D6 allele was isolated from leukocyte DNA of an individual who was deficient in debrisoquine metabolism. The gene was completely sequenced, including 725 bp of upstream and 400 bp of downstream DNA. Several base changes were uncovered within the exons, resulting in four amino acid differences between the mutant and wild-type allele. Most important, a single base change G1934----A at the junction of the third intron and four exon would result in an incorrectly spliced primary transcript and in an mRNA having a single base deletion. This deletion presumably disrupts the mRNA reading frame, resulting in a truncated protein. These data establish unequivocally that the debrisoquine polymorphism is the result of mutant CYP2D6 alleles and provide a framework to design a genetic test for this drug oxidation deficiency. A defective CYP2D7 allele was also isolated and completely sequenced, providing evidence that gene conversions have occurred between CYP2D6 and CYP2D7.

Full text

PDF
994

Images in this article

1000Figure 3
on p.1000

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Deininger P. L. Random subcloning of sonicated DNA: application to shotgun DNA sequence analysis. Anal Biochem. 1983 Feb 15;129(1):216–223. doi: 10.1016/0003-2697(83)90072-6. [DOI] [PubMed] [Google Scholar]
  2. Gonzalez F. J., Nebert D. W. Evolution of the P450 gene superfamily: animal-plant 'warfare', molecular drive and human genetic differences in drug oxidation. Trends Genet. 1990 Jun;6(6):182–186. doi: 10.1016/0168-9525(90)90174-5. [DOI] [PubMed] [Google Scholar]
  3. Gonzalez F. J., Skoda R. C., Kimura S., Umeno M., Zanger U. M., Nebert D. W., Gelboin H. V., Hardwick J. P., Meyer U. A. Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature. 1988 Feb 4;331(6155):442–446. doi: 10.1038/331442a0. [DOI] [PubMed] [Google Scholar]
  4. Gonzalez F. J., Vilbois F., Hardwick J. P., McBride O. W., Nebert D. W., Gelboin H. V., Meyer U. A. Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Genomics. 1988 Feb;2(2):174–179. doi: 10.1016/0888-7543(88)90100-0. [DOI] [PubMed] [Google Scholar]
  5. Heim M., Meyer U. A. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet. 1990 Sep 1;336(8714):529–532. doi: 10.1016/0140-6736(90)92086-w. [DOI] [PubMed] [Google Scholar]
  6. Idle J. R., Smith R. L. Polymorphisms of oxidation at carbon centers of drugs and their clinical significance. Drug Metab Rev. 1979;9(2):301–317. doi: 10.3109/03602537908993896. [DOI] [PubMed] [Google Scholar]
  7. Kagimoto M., Heim M., Kagimoto K., Zeugin T., Meyer U. A. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine. Study of the functional significance of individual mutations by expression of chimeric genes. J Biol Chem. 1990 Oct 5;265(28):17209–17214. [PubMed] [Google Scholar]
  8. Kimura S., Umeno M., Skoda R. C., Meyer U. A., Gonzalez F. J. The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet. 1989 Dec;45(6):889–904. [PMC free article] [PubMed] [Google Scholar]
  9. Loenen W. A., Brammar W. J. A bacteriophage lambda vector for cloning large DNA fragments made with several restriction enzymes. Gene. 1980 Aug;10(3):249–259. doi: 10.1016/0378-1119(80)90054-2. [DOI] [PubMed] [Google Scholar]
  10. Matsunaga E., Umeno M., Gonzalez F. J. The rat P450 IID subfamily: complete sequences of four closely linked genes and evidence that gene conversions maintained sequence homogeneity at the heme-binding region of the cytochrome P450 active site. J Mol Evol. 1990 Feb;30(2):155–169. doi: 10.1007/BF02099942. [DOI] [PubMed] [Google Scholar]
  11. Nebert D. W., Nelson D. R., Adesnik M., Coon M. J., Estabrook R. W., Gonzalez F. J., Guengerich F. P., Gunsalus I. C., Johnson E. F., Kemper B. The P450 superfamily: updated listing of all genes and recommended nomenclature for the chromosomal loci. DNA. 1989 Jan-Feb;8(1):1–13. doi: 10.1089/dna.1.1989.8.1. [DOI] [PubMed] [Google Scholar]
  12. Schmid B., Bircher J., Preisig R., Küpfer A. Polymorphic dextromethorphan metabolism: co-segregation of oxidative O-demethylation with debrisoquin hydroxylation. Clin Pharmacol Ther. 1985 Dec;38(6):618–624. doi: 10.1038/clpt.1985.235. [DOI] [PubMed] [Google Scholar]
  13. Skoda R. C., Gonzalez F. J., Demierre A., Meyer U. A. Two mutant alleles of the human cytochrome P-450db1 gene (P450C2D1) associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5240–5243. doi: 10.1073/pnas.85.14.5240. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES