Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1989 Dec;45(6):889–904.

The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene.

S Kimura 1, M Umeno 1, R C Skoda 1, U A Meyer 1, F J Gonzalez 1
PMCID: PMC1683468  PMID: 2574001

Abstract

The debrisoquine-4-hydroxylase polymorphism is a genetic variation in oxidative drug metabolism characterized by two phenotypes, the extensive metabolizer (EM) and poor metabolizer (PM). Of the Caucasian populations of Europe and North America, 5%-10% are of the PM phenotype and are unable to metabolize debrisoquine and numerous other drugs. The defect is caused by several mutant alleles of the CYP2D6 gene, two of which are detected in about 70% of PMs. We have constructed a genomic library from lymphocyte DNA of an EM positively identified by pedigree analysis to be homozygous for the normal CYP2D6 allele. The normal CYP2D6 gene was isolated; was completely sequenced, including 1,531 and 3,522 bp of 5' and 3' flanking DNA, respectively; and was found to contain nine exons within 4,378 bp. Two other genes, designated CYP2D7 and CYP2D8P, were also cloned and sequenced. CYP2D8P contains several gene-disrupting insertions, deletions, and termination codons within its exons, indicating that this is a pseudogene. CYP2D7, which is just downstream of CYP2D8P, is apparently normal, except for the presence, in the first exon, of an insertion that disrupts the reading frame. A hypothesis is presented that the presence of a pseudogene within the CYP2D subfamily transfers detrimental mutations via gene conversions into the CYP2D6 gene, thus accounting for the high frequency of mutations observed in the CYP2D6 gene in humans.

Full text

PDF
889

Images in this article

891Figure 1
on p.891
893Figure 3
on p.893

Selected References

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

  1. Daar I. O., Maquat L. E. Premature translation termination mediates triosephosphate isomerase mRNA degradation. Mol Cell Biol. 1988 Feb;8(2):802–813. doi: 10.1128/mcb.8.2.802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Distlerath L. M., Reilly P. E., Martin M. V., Davis G. G., Wilkinson G. R., Guengerich F. P. Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J Biol Chem. 1985 Jul 25;260(15):9057–9067. [PubMed] [Google Scholar]
  4. Eichelbaum M. Polymorphic oxidation of debrisoquine and sparteine. Prog Clin Biol Res. 1986;214:157–167. [PubMed] [Google Scholar]
  5. Gonzalez F. J., Matsunaga T., Nagata K., Meyer U. A., Nebert D. W., Pastewka J., Kozak C. A., Gillette J., Gelboin H. V., Hardwick J. P. Debrisoquine 4-hydroxylase: characterization of a new P450 gene subfamily, regulation, chromosomal mapping, and molecular analysis of the DA rat polymorphism. DNA. 1987 Apr;6(2):149–161. doi: 10.1089/dna.1987.6.149. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Gonzalez F. J. The molecular biology of cytochrome P450s. Pharmacol Rev. 1988 Dec;40(4):243–288. [PubMed] [Google Scholar]
  8. 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]
  9. Gut J., Catin T., Dayer P., Kronbach T., Zanger U., Meyer U. A. Debrisoquine/sparteine-type polymorphism of drug oxidation. Purification and characterization of two functionally different human liver cytochrome P-450 isozymes involved in impaired hydroxylation of the prototype substrate bufuralol. J Biol Chem. 1986 Sep 5;261(25):11734–11743. [PubMed] [Google Scholar]
  10. 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]
  11. Larrey D., Distlerath L. M., Dannan G. A., Wilkinson G. R., Guengerich F. P. Purification and characterization of the rat liver microsomal cytochrome P-450 involved in the 4-hydroxylation of debrisoquine, a prototype for genetic variation in oxidative drug metabolism. Biochemistry. 1984 Jun 5;23(12):2787–2795. doi: 10.1021/bi00307a039. [DOI] [PubMed] [Google Scholar]
  12. McBride O. W., Merry D., Givol D. The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proc Natl Acad Sci U S A. 1986 Jan;83(1):130–134. doi: 10.1073/pnas.83.1.130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Miller W. L. Gene conversions, deletions, and polymorphisms in congenital adrenal hyperplasia. Am J Hum Genet. 1988 Jan;42(1):4–7. [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Nelson D. R., Strobel H. W. Evolution of cytochrome P-450 proteins. Mol Biol Evol. 1987 Nov;4(6):572–593. doi: 10.1093/oxfordjournals.molbev.a040471. [DOI] [PubMed] [Google Scholar]
  16. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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