Debrisoquine and metoprolol oxidation in Zambians: a population study

Oo, Simooya; E, Njunju; Ar, Hodjegan; Ms, Lennard; Tucker, GT

doi:10.1097/00008571-199308000-00005

Cited by 23 publications

(9 citation statements)

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“…Furthermore, cases of genotype to phenotype discordance have been described in a number of studies, but remain unresolved. [17][18][19][20][21][22][23][24] The presence of the reduced function alleles CYP2D6*17 and *29 partially explain lower activity in Blacks, but additional nonfunctional alleles and alleles encoding protein with reduced enzymatic properties likely exist.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

et al. 2005

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Cytochrome P4502D6 (CYP2D6) genotyping reliably predicts poor metabolizer phenotype in Caucasians, but is less accurate in African Americans. To evaluate discordance we have observed in phenotype to genotype correlation studies, select African American subjects were chosen for complete resequencing of the CYP2D6 gene including 4.2 kb of the CYP2D7-2D6 intergenic region. Comparisons were made to a CYP2D6*1 reference sequence revealing novel SNPs in the upstream, coding and intervening sequences. These sequence variations, defining four functional alleles (CYP2D6*41B, *45A and B and *46), were characterized for their ability to influence splice site strength, transcription level or catalytic protein activity. Furthermore, their frequency was determined in a population of 251 African Americans. A À692 TGTG deletion (CYP2D6*45B) did not significantly decrease gene expression, nor could any other upstream SNP explain a genotype-discordant case. CYP2D6*45 and *46 have a combined frequency of 4% and can be identified by a common SNP. Carriers are predicted to exhibit an extensive or intermediate CYP2D6 phenotype.

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Section: Introductionmentioning

confidence: 99%

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

et al. 2005

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“…Black African populations are notable for the presence of the CYP2D6*17 allele, which occurs at a frequency as high as 34% in studied populations (Bradford et al, 1998), and for an apparent lack of coregulatory control between debrisoquine and sparteine phenotypes (Woolhouse et al, 1985;Lennard et al, 1992) and debrisoquine and metoprolol phenotypes (Sommers et al, 1989;Simooya et al, 1993;Masimirembwa et al, 1996a). The CYP2D6*17 allele, which has been observed to have reduced activity in vitro (Oscarson et al, 1997), is therefore likely to be at least partially responsible for the lower CYP2D6 activity observed in black African populations (Masimirembwa et al, 1996b;Griese et al, 1999;Wennerholm et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…The intrinsic clearance (estimated as V max /K m ) of all three substrates (dextromethorphan, Droll et al (1998) in Ghanaian volunteers. Since sparteine and metoprolol were not specifically investigated in this study, it is not possible to address the effects of CYP2D6.17 on their metabolism nor the contribution of CYPD26.17 to the poor correlations between these two phenotyping probes and debrisoquine in vivo (Woolhouse et al, 1985;Sommers et al, 1989;Lennard et al, 1992;Simooya et al, 1993;Masimirembwa et al, 1996a;Droll et al, 1998). A novel variant allele with reduced functional activity, CYP2D6*29, was recently discovered at a frequency of 20% in a black Tanzanian population (Wennerholm et al, 2001) compared with only one allele observed in 672 European subjects (Marez et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, comparative phenotyping studies conducted in Ghanaian (Woolhouse et al, 1985) and Nigerian (Lennard et al, 1992) healthy volunteers provided evidence that CYP2D6 phenotyping probes, particularly sparteine and debrisoquine, are not coordinately regulated in these studied populations. A lack of coordinate regulation has also been reported between debrisoquine and metoprolol in Venda (Sommers et al, 1989), Zambian (Simooya et al, 1993), and Ghanaian (Masimirembwa et al, 1996a) subjects.…”

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confidence: 92%

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Characterization of Cytochrome P450 2D6.1 (CYP2D6.1), CYP2D6.2, and CYP2D6.17 Activities toward Model CYP2D6 Substrates Dextromethorphan, Bufuralol, and Debrisoquine

Marcucci

Pearce²,

Crespi³

et al. 2002

Drug Metabolism and Disposition

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ABSTRACT:Over 50 allelic variants of cytochrome P450 2D6 (CYP2D6) encoding fully functional, reduced-activity, or nonfunctional proteins have been described. Compared with Caucasians, studies in black populations demonstrate a tendency toward slower CYP2D6 activity, attributed in part to the presence of a variant allele associated with reduced activity, the CYP2D6*17 allele. To investigate the kinetic characteristics of this variant protein, expression constructs coding for CYP2D6.1, CYP2D6.2, and CYP2D6.17 gene products were prepared and transfected into mammalian COS-7 and insect (Trichoplusia ni) cells for expression. Microsomal fractions containing the expressed proteins were used to determine the kinetic parameters K m , V max , and intrinsic clearance (Cl int ) for the model substrates dextromethorphan, bufuralol, and debrisoquine. Relative to the wild-type CYP2D6.1 protein expressed in COS-7 cells, CYP2D6.17 exhibited a 2-fold higher K m and a 50% reduction in V max using dextromethorphan as the substrate. In contrast, no appreciable change in bufuralol K m was observed with CYP2D6.17 whereas V max was decreased by 50%. When expressed in the baculovirus expression system, CYP2D6.17 exhibited a 6-fold increase in K m but no change in V max with dextromethorphan as the substrate, a 2-fold higher K m and 50% reduction in V max with bufuralol, and a 3-fold increase in K m and no change in V max with debrisoquine relative to CYP2D6.1. These data indicate that CYP2D6.17 exhibits reduced metabolic activity toward all three commonly used CYP2D6 substrates, although specific effects on substrate affinity and turnover demonstrate some substrate dependence.

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“…Formation of c~-hydroxymetoprolol, has been shown to co-segregate with debrisoquine hydroxylase in Caucasians (Lennard 1982;Lennard andSilas 1983, Lennard et al 1986). However, a dissociation in the control of debrisoquine and metoprolol oxidation has been observed in African populations (Simooya et al 1993;Lennard et al 1992). The purpose of this work was to compare the pattern of metoprolol a-hydroxylation with debrisoquine 4-hydroxylation among a group of Jordanian subjects, and to evaluate the applicability of the log metoprolol/c~-hydroxymetoprolol ratio in identifying the metabolizer status of the debrisoquine type.…”

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confidence: 99%

Metoprolol ?-hydroxylation is a poor probe for debrizoquine oxidation (CYP2D6) polymorphism in Jordanians

Al-Hadidi

Irshaid

Rawashdeh

1994

Eur J Clin Pharmacol

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The frequency distribution of the 8-h urinary ratio of log metoprolol/alpha-hydroxymetoprolol was assessed in 65 healthy, unrelated Jordanian volunteers. There was no apparent bimodality in the frequency distribution of this ratio among the subjects studied. The frequency of the poor metabolizer phenotype of metoprolol alpha-hydroxylation was 1.5% (one subject). There was a significant correlation (r = 0.61, P < 0.05, n = 39) between the log metoprolol/alpha-hydroxymetoprolol and the log debrisoquine/4-hydroxydebrisoquine ratios. However, the frequency of poor metabolizer status of debrisoquine among the 39 subjects was 7.7% (three subjects). Only one of the poor metabolizer of metoprolol alpha-hydroxylation. These findings indicate that metoprolol alpha-hydroxylation by CYP2D6 represents a poor probe for studying debrisoquine polymorphism in Jordanians.

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Debrisoquine and metoprolol oxidation in Zambians: a population study

Cited by 23 publications

References 0 publications

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

Identification and characterization of novel sequence variations in the cytochrome P4502D6 (CYP2D6) gene in African Americans

Characterization of Cytochrome P450 2D6.1 (CYP2D6.1), CYP2D6.2, and CYP2D6.17 Activities toward Model CYP2D6 Substrates Dextromethorphan, Bufuralol, and Debrisoquine

Metoprolol ?-hydroxylation is a poor probe for debrizoquine oxidation (CYP2D6) polymorphism in Jordanians

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