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

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Hemangeol, approved for the treatment of proliferative infantile hemangiomas requiring systemic therapy, is metabolized by cytochrome P450 2D6 (CYP2D6), which is a highly polymorphic enzyme that metabolizes a large number of drugs. More than 100 CYP2D6 allelic variants have been reported so far, including 22 novel variants that discovered in our lab in the Chinese population. Our study aimed to probe the enzymatic activity of these variants toward hemangeol in vitro with recombinant microsomes that expressed in sf21 insect cells using a baculovirus-mediated expression system.

Methods

The wild-type CYP2D6.1 and other variants (CYP2D6.2, CYP2D6.10 and 22 novel CYP2D6 variants) were incubated with 1–200 μM hemangeol for 50 min at 37 °C. Then the products were extracted, and signal detection was performed by high-performance liquid chromatography with fluorescence detector.

Results

All of the variants exhibited changed apparent Michaelis-Menten constant (Km) or maximum velocity of the reaction (V max) values compared with that of wild-type protein. The intrinsic clearances (V max /Km) were significantly decreased by 0.37 to 42.74 %. However, CYP2D6.92 and CYP2D6.96 showed no or minimal enzymatic activity as no concentration of 4′-hydroxypropranolol was detected.

Conclusions

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

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Acknowledgments

The authors thank the members of the Beijing Institute of Geriatrics of the Ministry of Health for their advice and assistance. This work was supported by the Ministry of Health of the People’s Republic of China (201302008).

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Authors and Affiliations

  1. School of Pharmacy, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People’s Republic of China

    Bingqing Liang, Yunyun Zhan, Xiangxin Huang, Ermin Gu & Guoxin Hu

  2. The Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing, 100730, People’s Republic of China

    Dapeng Dai & Jianping Cai

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  1. Bingqing Liang
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  2. Yunyun Zhan
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Correspondence to Jianping Cai or Guoxin Hu.

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Liang, B., Zhan, Y., Huang, X. et al. Effect of 22 Novel Cytochrome P450 2D6 (CYP2D6) Variants Found in the Chinese Population on Hemangeol Metabolism In Vitro. Eur J Drug Metab Pharmacokinet 41, 759–765 (2016). https://doi.org/10.1007/s13318-015-0307-0

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