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Mechanism-based inactivation of cytochrome P450 2D6 by Notopterol.
Chem Biol Interact. 2020 May 01; 322:109053.CB

Abstract

Notopterol (NOT) is a major bioactive ingredient extracted from the rhizomes of either Notopterygium incisum Ting ex H. T. Chang or N. forbesii Boiss (Qianghuo in Chinese), a botanical drug that was adopted as a traditional Chinese medicine. NOT is suggested to show analgesic and anti-inflammatory effects in clinical practice. The inhibitory effects of NOT on human cytochrome P450 enzymes were investigated in the present study. Our results indicate that NOT inhibited the activity of CYP2D6 in a time-, concentration- and NADPH-dependent manner. The values of KI and kinact were 10.8 μM and 0.62 min-1, respectively. The calculated kobs at 10 μM was 0.29 min-1, above the 0.02 min-1 risk level. After incubation with NOT at 10 μM for 9 min, approximately 92% of CYP2D6 activity was inhibited. Such loss of enzyme activity was not restored through dialysis, which indicates that the observed enzyme inhibition was irreversible. Partition ratio of the inactivation was approximately 29. Quinidine, a competitive CYP2D6 inhibitor, demonstrated protection on enzymes against the NOT-induced inactivation, but such protection was not found in incubation systems fortified with glutathione or catalase/superoxide dismutase. Additionally, CYP3A4 was observed to function as an enzyme mainly involved in the biotransformation of NOT. Taken together, these findings indicate that NOT served as a mechanism-based inactivator of CYP2D6, meanwhile, those observed effects may induce the latent drug-drug interactions. The metabolic activation of NOT may be the key to trigger the inactivation of the enzyme.

Authors+Show Affiliations

Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China.Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China. Electronic address: yingpeng1999@163.com.Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, PR China; State Key Laboratory of Functions and Applications of Medicinal Plants, Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, 550025, PR China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, PR China. Electronic address: zhengneu@yahoo.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32198085

Citation

Fu, Yao, et al. "Mechanism-based Inactivation of Cytochrome P450 2D6 By Notopterol." Chemico-biological Interactions, vol. 322, 2020, p. 109053.
Fu Y, Tian X, Han L, et al. Mechanism-based inactivation of cytochrome P450 2D6 by Notopterol. Chem Biol Interact. 2020;322:109053.
Fu, Y., Tian, X., Han, L., Li, Y., Peng, Y., & Zheng, J. (2020). Mechanism-based inactivation of cytochrome P450 2D6 by Notopterol. Chemico-biological Interactions, 322, 109053. https://doi.org/10.1016/j.cbi.2020.109053
Fu Y, et al. Mechanism-based Inactivation of Cytochrome P450 2D6 By Notopterol. Chem Biol Interact. 2020 May 1;322:109053. PubMed PMID: 32198085.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism-based inactivation of cytochrome P450 2D6 by Notopterol. AU - Fu,Yao, AU - Tian,Xiaoxiao, AU - Han,Lingling, AU - Li,Yilin, AU - Peng,Ying, AU - Zheng,Jiang, Y1 - 2020/03/19/ PY - 2019/10/24/received PY - 2020/01/28/revised PY - 2020/03/09/accepted PY - 2020/3/22/pubmed PY - 2020/4/14/medline PY - 2020/3/22/entrez KW - CYP450 KW - Mechanism-based inactivation KW - Notopterol SP - 109053 EP - 109053 JF - Chemico-biological interactions JO - Chem. Biol. Interact. VL - 322 N2 - Notopterol (NOT) is a major bioactive ingredient extracted from the rhizomes of either Notopterygium incisum Ting ex H. T. Chang or N. forbesii Boiss (Qianghuo in Chinese), a botanical drug that was adopted as a traditional Chinese medicine. NOT is suggested to show analgesic and anti-inflammatory effects in clinical practice. The inhibitory effects of NOT on human cytochrome P450 enzymes were investigated in the present study. Our results indicate that NOT inhibited the activity of CYP2D6 in a time-, concentration- and NADPH-dependent manner. The values of KI and kinact were 10.8 μM and 0.62 min-1, respectively. The calculated kobs at 10 μM was 0.29 min-1, above the 0.02 min-1 risk level. After incubation with NOT at 10 μM for 9 min, approximately 92% of CYP2D6 activity was inhibited. Such loss of enzyme activity was not restored through dialysis, which indicates that the observed enzyme inhibition was irreversible. Partition ratio of the inactivation was approximately 29. Quinidine, a competitive CYP2D6 inhibitor, demonstrated protection on enzymes against the NOT-induced inactivation, but such protection was not found in incubation systems fortified with glutathione or catalase/superoxide dismutase. Additionally, CYP3A4 was observed to function as an enzyme mainly involved in the biotransformation of NOT. Taken together, these findings indicate that NOT served as a mechanism-based inactivator of CYP2D6, meanwhile, those observed effects may induce the latent drug-drug interactions. The metabolic activation of NOT may be the key to trigger the inactivation of the enzyme. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/32198085/Mechanism-based_inactivation_of_cytochrome_P450_2D6_by_Notopterol L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(19)31776-4 DB - PRIME DP - Unbound Medicine ER -