title: Inhibition of melatonin metabolism in humans induced by chemical components from herbs and effective prediction of this risk using a computational model.
abstract: Herbs which are widely used as food and medicine, are involved in many physiopathological processes. Melatonin is a human hormone, synthesized and secreted by the pineal gland, with a range of biological functions. Here, we have evaluated the potential influences of components extracted from common herbs on melatonin metabolism in humans.
  
  
  
  An in vivo pharmacokinetic study involving 12 healthy subjects, in vitro incubations with human liver microsomes (HLMs) and recombinant human cytochrome P (CYP) isoenzymes and an in silico quantitative structure-activity relationship (QSAR) model analysis using comparative molecular field analysis and comparative molecular similarity indices analysis methods were employed to explore these interactions.
  
  
  
  After systematic screening of 66 common herbs, Angelica dahurica exhibited the most potent inhibition of melatonin metabolism in vitro. The in vivo pharmacokinetic study indicated inhibition of melatonin metabolism, with approximately 12- and 4-fold increases in the AUC and Cmaxof melatonin in human subjects. Coumarins from A. dahurica, including imperatorin, isoimperatorin, phellopterin, 5-methoxypsoralen and 8-methoxypsoralen, markedly inhibited melatonin metabolism with Kivalues of 14.5 nM, 38.8 nM, 6.34 nM, 5.34 nM and 18 nM respectively, through inhibition of CYP 1A2, 1A1 and 1B1 in HLMs. A QSAR model was established and satisfactorily predicted the potential risk of coumarins for inhibition of melatonin metabolism in vivo.
  
  
  
  Coumarins from A. dahurica inhibited melatonin metabolism in vivo and in vitro. Our findings provide vital guidance for the clinical use of melatonin.
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.|Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors: Chao
authors: C
authors: Wang
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors: Xiaokui
authors: X
authors: Huo
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors: Xiangge
authors: X
authors: Tian
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors: Min
authors: M
authors: Xu
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors: Peipei
authors: P
authors: Dong
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors: Zhilin
authors: Z
authors: Luan
authors: Department of Pharmacy and Traditional Chinese Medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China.
authors: Xiaobo
authors: X
authors: Wang
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors: Baojing
authors: B
authors: Zhang
authors: Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China. zhangbodl@126.com.
authors: Bo
authors: B
authors: Zhang
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors: Shanshan
authors: S
authors: Huang
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China.
authors: Sa
authors: S
authors: Deng
authors: Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China. maxc1978@163.com.|Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China. maxc1978@163.com.
authors: Xiaochi
authors: X
authors: Ma
mesh_terms: D029969:Angelica / Q000737:chemistry*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D008550:Melatonin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D012307:Risk Factors
chemical_list: D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D008550:Melatonin