Decreased capacity for debrisoquine metabolism among black Tanzanians

Wennerholm, Agneta; Johansson, Inger; Massele, Amos; Jande, Mary; Alm, Christina; Aden-Abdi, Y.; Ingelman-Sundberg, Magnus; Gustafsson, Lars L.

doi:10.1097/01213011-199912000-00005

Cited by 23 publications

(33 citation statements)

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“…Sistonen et al investigated CYP2D6 haplotype frequencies in single populations, and in Cambodia they found no polymorphisms in CYP2D6*4 or CYP2D6*17 genes but a 54.5% mutation rate in CYP2D6*10 (34), which is comparable with our data. A study on CYP2D6 genotypes in Tanzania also reported a low allele frequency for CYP2D6*4 (1%) and an intermediate frequency for CYP2D6*17 (17%) (36), while for the latter we found a much higher frequency (60.6%). As for CYP2C19*3, the observed low frequency confirmed previous findings from a study for Tanzania, where no CYP2C19*3 alleles were found (37).…”

Section: Discussionmentioning

confidence: 50%

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

Hodel

Csajka

Ariey

et al. 2013

Antimicrob Agents Chemother

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The pharmacogenetics of antimalarial agents are poorly known, although the application of pharmacogenetics might be critical in optimizing treatment. This population pharmacokinetic-pharmacogenetic study aimed at assessing the effects of single nucleotide polymorphisms (SNPs) in cytochrome P450 isoenzyme genes (CYP, namely, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5) and the N-acetyltransferase 2 gene (NAT2) on the pharmacokinetics of artemisininbased combination therapies in 150 Tanzanian patients treated with artemether-lumefantrine, 64 Cambodian patients treated with artesunate-mefloquine, and 61 Cambodian patients treated with dihydroartemisinin-piperaquine. The frequency of SNPs varied with the enzyme and the population. Higher frequencies of mutant alleles were found in Cambodians than Tanzanians for CYP2C9*3, CYP2D6*10 (100C¡T), CYP3A5*3, NAT2*6, and NAT2*7. In contrast, higher frequencies of mutant alleles were found in Tanzanians for CYP2D6*17 (1023C¡T and 2850C¡T), CYP3A4*1B, NAT2*5, and NAT2*14. For 8 SNPs, no significant differences in frequencies were observed. In the genetic-based population pharmacokinetic analyses, none of the SNPs improved model fit. This suggests that pharmacogenetic data need not be included in appropriate first-line treatments with the current artemisinin derivatives and quinolines for uncomplicated malaria in specific populations. However, it cannot be ruled out that our results represent isolated findings, and therefore more studies in different populations, ideally with the same artemisininbased combination therapies, are needed to evaluate the influence of pharmacogenetic factors on the clearance of antimalarials.

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Section: Discussionmentioning

confidence: 50%

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

Hodel

Csajka

Ariey

et al. 2013

Antimicrob Agents Chemother

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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). However, its contribution to the observed discrepancies in phenotype assignment noted above has not been addressed.…”

Section: Discussionmentioning

confidence: 69%

“…CYP2D6 phenotyping studies indicate that Chinese (Bertilsson et al, 1992) and individuals of black African origin (Woolhouse et al, 1985;Masimirembwa et al, 1996a;Wennerholm et al, 1999) tend to have lower CYP2D6 activity on a population basis, relative to Caucasians. 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).…”

Section: Discussionmentioning

confidence: 99%

“…By analysis of CYP2D6 genotype, a poor metabolizer phenotype can be reliably assigned based on the finding of two nonfunctional or "null" alleles and can be confirmed in affected individuals using currently available CYP2D6 phenotyping probe drugs, such as dextromethorphan, sparteine, or debrisoquine (Marez et al, 1997;Sachse et al, 1997;Gaedigk et al, 1999). In contrast, population studies in Africans have generally observed CYP2D6 activity to be unimodally distributed with a tendency toward higher urinary metabolite ratios (lower enzyme activity) compared with that observed in Caucasian populations (Woolhouse et al, 1985;Masimirembwa et al, 1996a;Wennerholm et al, 1999), a finding that is now attributed to a relatively high frequency (17-30%) of the CYP2D6*17 1 allele (Masimirembwa et al, 1996b). 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.…”

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confidence: 99%

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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 Metab Dispos

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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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“…These genetic differences probably explain the differences observed in the current study in that the allelic frequencies of the CYP2D6*17 and CYP2D6*29 alleles were 20.9 and 7.2%, respectively, in the liver samples from AfricanAmerican donors in contrast to 1.3 and 0%, respectively, in the liver samples from Caucasian donors. However, extrapolation of these genotypes to phenotypes is complicated by evidence of altered substrate specificity for CYP2D6*17 and CYP2D6*29, such that the concordance between phenotype is dependent upon the probe substrate used and the genotypic composition of the ethnic population under investigation (Wennerholm et al, 1999(Wennerholm et al, , 2001). CYP2D6 probedependent analysis was not feasible for the current study because of constraints with tissue sample amounts.…”

Section: Discussionmentioning

confidence: 99%

Developmental Changes in Human Liver CYP2D6 Expression

Stevens

Marsh²,

Zaya³

et al. 2008

Drug Metab Dispos

134

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ABSTRACT:Within the human cytochrome P450 family, specific forms show developmental expression patterns that can affect drug clearance, efficacy, and safety. The objective of this study was to use dextromethorphan O-demethylase activity and quantitative Western blotting to identify CYP2D6 developmental expression patterns in a large (n ‫؍‬ 222) and developmentally diverse set of pediatric liver samples. Immunodetectable levels of CYP2D6 protein determined for selected samples across all age categories showed a significant correlation with the corresponding dextromethorphan O-demethylase activity. Of gender, ethnicity, postmortem interval, and genotype, only increasing gestational age was associated with CYP2D6 activity and protein content in prenatal samples. In contrast, both age and genotype were associated with CYP2D6 expression in postnatal samples. CYP2D6 expression in liver samples from neonates less than 7 days of age was higher than that observed in first and second trimester samples, but not significantly higher than third trimester fetal samples. In contrast, expression in postnatal samples greater than 7 days of age was substantially higher than that for any earlier age category. Higher CYP2D6 expression also was observed in liver samples from Caucasians versus African Americans. Finally, using phenotype categories inferred from genotype, CYP2D6 activity was higher in postnatal samples predicted to be extensive or intermediate metabolizers versus poor metabolizers. These results suggest that age and genetic determinants of CYP2D6 expression constitute significant determinants of interindividual variability in CYP2D6-dependent metabolism during ontogeny.

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Decreased capacity for debrisoquine metabolism among black Tanzanians

Cited by 23 publications

References 0 publications

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

Effect of Single Nucleotide Polymorphisms in Cytochrome P450 Isoenzyme and N -Acetyltransferase 2 Genes on the Metabolism of Artemisinin-Based Combination Therapies in Malaria Patients from Cambodia and Tanzania

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

Developmental Changes in Human Liver CYP2D6 Expression

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