Effect of 22 Novel Cytochrome P450 2D6 (CYP2D6) Variants Found in the Chinese Population on Hemangeol Metabolism In Vitro

Liang, Bo; Zhan, Yun-Yun; Huang, Xiang-Xin; Gu, Er-min; Dai, Da‐Peng; Cai, Jianping; Hu, Guoxin

doi:10.1007/s13318-015-0307-0

Cited by 7 publications

(8 citation statements)

References 23 publications

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“…The latter amino acid substitution has been shown to cause protein instability and reduced substrate affinity (Wang et al, 1999). As reported by previous studies, CYP2D6.10 yields 1.34%-4.57% of the efficiency of CYP2D6*1 toward bufuralol (1.34%), propranolol (1.41%), risperidone (2.01%), venlafaxine (2.90%), and dextromethorphan (4.57%) in vitro (Liang et al, 2015;Wang et al, 2015;Cai et al, 2016;Zhan et al, 2016). In our study, CYP2D6.10 had a decreased V max (8.71%), an increased K m (3.62-fold), and a significantly decreased intrinsic clearance (4.07%) of nebivolol compared with CYP2D6.1.…”

Section: Resultssupporting

confidence: 80%

Evaluation of 24 CYP2D6 Variants on the Metabolism of Nebivolol In Vitro

Lan

Dai

et al. 2016

Drug Metabolism and Disposition

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CYP2D6 is an important cytochrome P450 (P450) enzyme that metabolizes approximately 25% of therapeutic drugs. Its genetic polymorphisms may significantly influence the pharmacokinetics and pharmacodynamics of clinically used drugs. Studying the effects of CYP2D6 on drug metabolism can help reduce adverse drug reactions and therapeutic failure to some extent. This study aimed to investigate the role of CYP2D6 in nebivolol metabolism by evaluating the effect of 24 CYP2D6 variants on the metabolism of nebivolol in vitro. CYP2D6 variants expressed by insect cell systems were incubated with 0.1-80 μM nebivolol for 30 minutes at 37°C and the reaction was terminated by cooling to -80°C immediately. An ultra-performance liquid chromatography-tandem mass spectrometry system was used to analyze nebivolol and its metabolite 4-hydroxy nebivolol. Compared with CYP2D6.1, the intrinsic clearance values of most variants were significantly altered, and most of these variants exhibited either reduced V and/or increased K values. Variant R440C showed much higher intrinsic clearance than the wild type (219.08%). Five variants (CYP2D6.88, CYP2D6.89, R344Q, V342M, and D336N) exhibited no difference from the wild type. CYP2D6.92 and CYP2D6.96 displayed weak or no activity, whereas the intrinsic clearance values of the remaining 16 variants were significantly reduced to various degrees (ranging from 4.07% to 71%). As the first report of 24 CYP2D6 alleles for nebivolol metabolism, these results are valuable to interpreting in vivo studies and may also serve as a reference for rational clinical administration.

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Section: Resultssupporting

confidence: 80%

Evaluation of 24 CYP2D6 Variants on the Metabolism of Nebivolol In Vitro

Lan

Dai

et al. 2016

Drug Metabolism and Disposition

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“…Furthermore, the most meaningful difference between our study and previous reports19,21–24 is that gefitinib exhibited a substrate inhibition trend of metabolic ability by CYP2D6 in vitro. Twenty-three tested CYP2D6 allelic variants showed this substrate inhibition trend toward gefitinib and their K si values varied from ~6 to 158 μM.…”

Section: Discussioncontrasting

confidence: 96%

“…In addition, different from the previous studies,19,21–24 the metabolic ability toward gefitinib in vitro exhibited substrate inhibition trend, the inhibition constant of 25 tested CYP2D6 variants varied from nearly 5.9 to 158.1 μM.…”

Section: Resultscontrasting

confidence: 86%

“…In our study, both CYP2D6.92 and CYP2D6.96 had undetectable enzyme activity in gefitinib metabolism, similar to previous reports 19,21,23,24. The reason for this may be because both of these variants were expressed as truncated proteins due to the premature termination in protein translation process, which led to the function loss of enzymatic activity.…”

Section: Discussionsupporting

confidence: 89%

“…Particularly, only one variant CYP2D6.94, with a decrease K m and an increase V max , showed significant increased relative clearance compared with CYP2D6.1, suggesting higher catalytic activity than CYP2D6.1. On the contrary, as reported in other studies, CYP2D6.94 exhibited markedly different decreased catalytic activity toward propranolol (31.37%), nebivolol (58.23%), dextromethorphan (67.03%), venlafaxine (71.9%), and bufuralol (74.96%) in vitro 19,21,23,24. These data suggest that CYP2D6.94 may be reclassified as an ultrarapid metabolizer phenotype for gefitinib.…”

Section: Discussionmentioning

confidence: 49%

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Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

Fang

Zheng

et al. 2017

DDDT

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BackgroundCytochrome P450 2D6 (CYP2D6), a member of the CYP450 enzyme super family, is a polymorphic enzyme that metabolizes ~25% of therapeutic drugs. CYP2D6 exhibits significant genetic polymorphisms which might cause adverse effects and therapeutic failures of some drugs.ObjectiveThe purpose of this study was to evaluate the catalytic activities of 22 novel CYP2D6 alleles (CYP2D6*87, *88, *89, *90, *91, *92, *93, *94, *95, *96, *97, *98, R25Q, F164L, E215K, F219S, V327M, D336N, V342M, R344Q, R440C, R497C) on the metabolism of gefitinib in vitro.Methods and resultsCYP2D6 variants were incubated with 1–100 μM gefitinib for 60 min at 37°C and the reaction was terminated by cooling to −80°C immediately. Gefitinib and its metabolite O-desmethyl gefitinib were analyzed by an ultra-performance liquid chromatography-tandem mass spectrometry system. Compared to CYP2D6.1, most CYP2D6 variants exhibited significantly decreased relative clearance values (from 3.11% to 79.35%), whereas CYP2D6.92 and CYP2D6.96 displayed no detectable enzyme activity. Only CYP2D6.94 exhibited a markedly increased intrinsic clearance value, and eight variants (CYP2D6.88, CYP2D6.89, CYP2D6.91, CYP2D6.97, V342M, R344Q, F219S, and F164L) showed no significant difference. In addition, 23 CYP2D6 allelic isoforms exhibited substrate inhibition trend toward gefitinib.ConclusionAs the first study of all the aforementioned alleles for gefitinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism of gefitinib, and may also offer a reference for personalized treatment with gefitinib in clinical settings.

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Comparative research on the metabolism of metoprolol by four CYP2D6 allelic variants in vitro with LC-MS/MS

Yang

Sun

et al. 2019

Journal of Pharmaceutical and Biomedical Analysis

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Effect of 22 Novel Cytochrome P450 2D6 (CYP2D6) Variants Found in the Chinese Population on Hemangeol Metabolism In Vitro

Abstract: The comprehensive in vitro assessment of CYP2D6 variants provides significant insights into allele-specific activity towards hemangeol in vivo.

Cited by 7 publications

References 23 publications

Evaluation of 24 CYP2D6 Variants on the Metabolism of Nebivolol In Vitro

Evaluation of 24 CYP2D6 Variants on the Metabolism of Nebivolol In Vitro

Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro

Comparative research on the metabolism of metoprolol by four CYP2D6 allelic variants in vitro with LC-MS/MS

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