Abstract
Objective
Many commonly used pharmaceuticals, such as antidepressants and neuroleptics as well as some illegal drugs, are metabolised by the cytochrome P 450 enzyme debrisoquine 4-hydroxylase (CYP2D6). Of Caucasians, 7–10% lack this enzyme, which can, upon administration of drugs in normal therapeutic doses, lead to adverse reactions and unexpected intoxication, leading in turn even to a fatal outcome in some cases.
Methods
Individuals (n=242) who had died due to intoxication by pharmaceuticals were genotyped for CYP2D6 and CYP2C19 and compared with a reference group of 281 blood donors. A single nucleotide polymorphism (SNP) method was used to identify five CYP2D6 alleles: *1 (wt), *2, *3, *4 and *6. The allele *5, a complete gene deletion, was identified by a multiplex amplification of long DNA fragments. Four CYP2C19 alleles *1 (wt), *2, *3 and *4 were also identified by SNP analysis.
Results
The prevalence of the CYP2D6 poor metaboliser (PM) genotypes in individuals with fatal intoxication was lower (4.7%) than expected from the frequencies of these genotypes in the blood donors (8.5%). A significantly lower frequency P<0.005 (0.03 with correction according to Bonferroni) was found for the CYP2D6*4 allele among the fatal intoxication cases. The CYP2C19 genotype analyses showed the same results for the fatal intoxication cases and for the blood donors.
Conclusions
The findings in this study confirm our earlier observations of a lower frequency of CYP2D6 PM genotypes in cases of fatal intoxication. To our knowledge, it has not been shown previously that intoxication victims might have a lower frequency of PMs than the general population.
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References
Brosen K (1996) Drug-metabolizing enzymes and therapeutic drug monitoring in psychiatry. Ther Drug Monit 18:393–396
Sachse C, Brockmoller J, Bauer S, Roots I (1997) Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet 60:284–295
Agundez JA, Ledesma MC, Ladero JM, Benitez J (1995) Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population. Clin Pharmacol Ther 57:265–269
Marez D, Legrand M, Sabbagh N, Guidice JM, Spire C, Lafitte JJ, Meyer UA, Broly F (1997) Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution. Pharmacogenetics 7:193–202
Sachse C, Brockmoller J, Hildebrand M, Muller K, Roots I (1998) Correctness of prediction of the CYP2D6 phenotype confirmed by genotyping 47 intermediate and poor metabolizers of debrisoquine. Pharmacogenetics 8:181–185
Goldstein JA, de Morais SM (1994) Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4:285–299
Alvan G, Bechtel P, Iselius L, Gundert-Remy U (1990) Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol 39:533–537
Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao XM, Wang KY, Reviriego J, Iselius L, Sjoqvist F (1992) Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 51:388–397
Chang M, Tybring G, Dahl ML, Gotharson E, Sagar M, Seensalu R, Bertilsson L (1995) Interphenotype differences in disposition and effect on gastrin levels of omeprazole—suitability of omeprazole as a probe for CYP2C19. Br J Clin Pharmacol 39:511–518
Druid H, Holmgren P, Carlsson B, Ahlner J (1999) Cytochrome P450 2D6 (CYP2D6) genotyping on postmortem blood as a supplementary tool for interpretation of forensic toxicological results. Forensic Sci Int 99:25–34
Holmgren P, Carlsson B, Zackrisson AL, Lindblom B, Dahl ML, Scordo MG, Druid H, Ahlner J (2004) Enantioselective analysis of citalopram and its metabolites in postmortem blood and genotyping for CYP2D6 and CYP2C19. J Appl Toxicol 28:94–105
Gustincich S, Manfioletti G, Del Sal G, Schneider C, Carninci P (1991) A fast method for high-quality genomic DNA extraction from whole human blood. Biotechniques 11:298–302
Ronaghi M, Karamohamed S, Pettersson B, Uhlen M, Nyren P (1996) Real-time DNA sequencing using detection of pyrophosphate release. Anal Biochem 242:84–89
Ahmadian A, Gharizadeh B, Gustafsson AC, Sterky F, Nyren P, Uhlen M, Lundeberg J (2000) Single-nucleotide polymorphism analysis by pyrosequencing. Anal Biochem 280:103–110
Zackrisson AL, Lindblom B (2003) Identification of CYP2D6 alleles by single nucleotide polymorphism analysis using pyrosequencing. Eur J Clin Pharmacol 59:521–526
Hersberger M, Marti-Jaun J, Rentsch K, Hanseler E (2000) Rapid detection of the CYP2D6*3, CYP2D6*4, and CYP2D6*6 alleles by tetra-primer PCR and of the CYP2D6*5 allele by multiplex long PCR. Clin Chem 46:1072–1077
Eriksson S, Berg LM, Wadelius M, Alderborn A (2002) Cytochrome P450 genotyping by multiplexed real-time dna sequencing with pyrosequencing technology. Assay Drug Dev Technol 1:49–59
Bonferroni CE (1936) Teoria statistica delle classi e calcolo delle probabilit ‘a. Pubblicazioni del R Istituto Superiore di Scienze Economiche e Commerciali di Firenze 8:3–62
Miller RG (1981) Simultaneous statistical inference, 2nd edn. Springer, Berlin Heidelberg New York
Kawanishi C, Lundgren S, Agren H, Bertilsson L (2004) Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol 59:803–807
Llerena A, Dorado P, Berecz R, Gonzalez AP, Penas LEM (2004) Effect of CYP2D6 and CYP2C9 genotypes on fluoxetine and norfluoxetine plasma concentrations during steady-state conditions. Eur J Clin Pharmacol 59:869–873
Wong SH, Wagner MA, Jentzen JM, Schur C, Bjerke J, Gock SB, Chang CC (2003) Pharmacogenomics as an aspect of molecular autopsy for forensic pathology/toxicology: does genotyping CYP 2D6 serve as an adjunct for certifying methadone toxicity? J Forensic Sci 48:1406–1415
Llerena A, Edman G, Cobaleda J, Benitez J, Schalling D, Bertilsson L (1993) Relationship between personality and debrisoquine hydroxylation capacity. Suggestion of an endogenous neuroactive substrate or product of the cytochrome P450 2D6. Acta Psychiatr Scand 87:23–28
Bertilsson L, Alm C, De Las Carreras C, Widen J, Edman G, Schalling D (1989) Debrisoquine hydroxylation polymorphism and personality. Lancet 1:555
Roberts RL, Luty SE, Mulder RT, Joyce PR, Kennedy MA (2004) Association between cytochrome P450 2D6 genotype and harm avoidance. Am J Med Genet 127B:90–93
Gan SH, Ismail R, Wan Adnan WA, Zulmi W, Kumaraswamy N, Larmie ET (2004) Relationship between type A and B personality and debrisoquine hydroxylation capacity. Br J Clin Pharmacol 57:785–789
Acknowledgements
This work has been supported by grants from the National Board of Forensic Medicine (Rättsmedicinalverket), Sweden.
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Zackrisson, A.L., Holmgren, P., Gladh, A.B. et al. Fatal intoxication cases: cytochrome P 450 2D6 and 2C19 genotype distributions. Eur J Clin Pharmacol 60, 547–552 (2004). https://doi.org/10.1007/s00228-004-0800-x
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DOI: https://doi.org/10.1007/s00228-004-0800-x