A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black African population: Association with diminished debrisoquine hydroxylase activity

British Journal of Clinical Pharmacology

Volumn 42, Issue 6, 1996, Pages 713-719

  Masimirembwa, Collen ^a   Persson, Irene ^a   Bertilsson, Leif ^b   Hasler, Julia ^c   Ingelman Sundberg, Magnus ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

^b KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^c UNIVERSITY OF ZIMBABWE   (Zimbabwe)

Author keywords

African population; Bantu; debrisoquine; drug metabolism; genetic polymorphism; interethnic differences; Zimbabwe

Indexed keywords

DEBRISOQUINE; DRUG METABOLITE;

AFRICA; ARTICLE; DRUG HYDROXYLATION; DRUG METABOLISM; ENZYME ACTIVITY; ETHNIC DIFFERENCE; GENETIC POLYMORPHISM; GENOTYPE; HOMOZYGOSITY; HUMAN; HUMAN EXPERIMENT; MUTATION; NORMAL HUMAN; PHENOTYPE; POPULATION; PRIORITY JOURNAL;

EID: 0029853664     PISSN: 03065251     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1365-2125.1996.00489.x     Document Type: Article

References (30)

1. Daly AK, Brockmöller J, Broly F, et al. Nomenclature for human CYP2D6 alleles, Pharmacogenetics 1996; 6: 193-201.
2. Eichelbaum M, Gross AS. The genetic polymorphism of debrisoquine/sparteine metabolism - clinical aspects. Pharmacol Ther 1990; 46: 377-394.
3. Sohn DR, Shin SG, Park CW, Kusaka M, Chiba K, Ishizaki T. Metoprolol oxidation polymorphism in a Korean population. Comparison with native Japanese and Chinese populations. Br J Clin Pharmacol 1991; 32: 504-507.
4. Alvan G, Bechtel P, Iselius L, Gundert-Remy U. Hydroxylation polymorphism of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 1990; 39: 533-537.
5. Lennard MS, Lyun AO, Jackson PR, Tucker GT, Woods HF. Evidence for dissociation in the control of sparteine, debrisoquine and metoprolol metabolism in Nigerians. Pharmacogenetics 1992; 2: 89-92.
6. Masimirembwa CM, Hasler JA, Bertilsson L, Johansson I, Ekberg O, Ingelman-Sundberg M. Phenotype- and genotype- analysis of debrisoquine hydroxylase (CYP2D6) in a black Zimbabwean population. Reduced enzyme activity and evaluation of metabolic correlation of CYP2D6 probe drugs. Eur J Clin Pharmacol 1996; (in press).
7. Skoda RC, Gonzalez FJ, Demierre A, and Meyer UA. Two mutant alleles of the human cytochrome P4502D6 gene associated with genetically deficient metabolism of debrisoquine and other drugs. Proc Natl Acad Sci USA 1988; 85: 5240-5243.
8. Broly F, Gaedig A, Heim M, Eichelbaum M, Morike K, Meyer UA. Debrisoquine/sparteine hydroxylation genotype and phenotype. Analysis of common mutations and alleles of CYP2D6 in a European population. DNA Cell Biol 1991; 10: 545-558.
9. Johansson I, Yue QY, Dahl ML, et al. Genetic analysis of the interethnic difference between Chinese and Caucasians in the polymorphic metabolism of debrisoquine and codeine. Eur J Clin Pharmacol 1991; 40: 553-556.
10. Masimirembwa CM, Johansson I, Hasler JA, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P450 2D6 in a Zimbabwean population. Pharmacogenetics 1993; 3: 275-280.
11. Saxena R, Shaw GL, Relling MV, et al. Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype. Hum Mol Genet 1994; 3: 923-926.
12. Bertilsson L, Lou YQ, Du YL, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquine and S-mephenytoin. Clin Pharmacol Ther 1992; 51: 388-397.
13. Bertilsson L, Dahl ML, Sjöqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 1993; 341: 63.
14. Kalow W, Bertilsson L. Interethnic factors affecting drug response. Adv Drug Res 1994; 25: 1-53.
15. Johansson I, Lundqvist E, Bertilsson L, Dahl ML, Sjöqvist F, Ingelman-Sundberg M. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Natl Acad Sci USA 1993; 90: 11825-11829.
16. Dahl ML, Johansson I, Bertilsson L, Ingelman-Sundberg M, Sjöqvist F. Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exp Ther 1995; 274: 516-520.
17. Agúndez, JAG, Ledesma, MC, Ladero, JM, and Benitez, J. Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin Pharmacol Ther 1995; 57: 265-269.
18. Yokota H, Tamura S, Furuya H, et al. Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with low in vivo rates of sparteine metabolism. Pharmacogenetics 1993; 3: 256-263.
19. Johansson I, Oscarson M, Yue QY, Bertilsson L, Sjöqvist F, Ingelman-Sundberg M. Genetic analysis of the Chinese cytochrome P4502D locus: Characterisation of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994; 46: 452-459.
20. Tyndale R, Aoyama T, Droly F, et al. Identification of a new variant CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metaboliser phenotype. Pharmacogenetics 1991; 1: 26-32.
21. Heim M, Meyer UA. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification. Lancet 1990; 336: 529-32.
22. Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ. 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; 45: 889-904.
23. Cavalli-Sforza LL, Piazza A, Menozzi P, Mountain J. Reconstruction of human evolution. Bring together genetic, archaeological, and linquistic data. Proc Natl Acad Sci USA 1988; 85: 6002-6006.
24. Aklillu E, Persson I, Bertilsson L, Johansson I, Rodrigues F, Ingelman-Sundberg M. Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Pharmacol Exp Ther 1996; 278: 441-446.
25. Koymans LMH, Vermeulen NDE, Baarslag A, Kelder D. A preliminary 3D model for cytochrome P450 2D6 constructed by homology model building. J Computer-Aided Molecular Design 1993; 7: 281-289.
26. Gotoh O. Substrate recognition sites in cytochrome P450 family 2 (CYP2). Proteins inferred from comparative analysis of amino acid and coding nucleotide sequences. J Biol Chem 1991; 267: 83-90.
27. Hasler JA, Harlow GR, Szklarz GD, et al. Site-directed mutagenesis of putative substrate recognition sites in cytochrome P450 2B11: Importance of amino acid residues 114, 290, and 363 for substrate specificity. Mol Pharmacol 1994; 46: 338-345.
28. Kagimoto M, Heim M, Kagimoto K, Zeugin T, Meyer UA. Multiple mutations of the human cytochrome P4502D6 gene in poor metabolisers of debrisoquine: study of the functional significance of individual mutation expression of chimeric genes. J Biol Chem 1990; 265: 17209-172016.
29. Lin KM, Poland RE, Smith MW, Strickland TL, Mendoza R. Pharmacokinetic and other related factors affecting psychotropic responses in Asians. Psychopharmacology Bulletin 1991; 27: 427-439.
30. Lou YC. Differences in drug metabolism polymorphism between Orientals and Caucasians. Drug Metab Rev 1990; 22: 451-475.