Chao Wang1,2, Xiaokui Huo1, Xiangge Tian1, Min Xu1, Peipei Dong1, Zhilin Luan1, Xiaobo Wang3, Baojing Zhang1, Bo Zhang4, Shanshan Huang1, Sa Deng1, Xiaochi Ma5,6. 1. Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China. 2. Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China. 3. Department of Pharmacy and Traditional Chinese Medicine, Chinese People's Liberation Army 210 Hospital, Dalian, China. 4. Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China. zhangbodl@126.com. 5. Academy of Integrative Medicine, College of Pharmacy, Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, Dalian Medical University, Dalian, China. maxc1978@163.com. 6. Department of Neurosurgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, China. maxc1978@163.com.
Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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 Cmax of melatonin in human subjects. Coumarins from A. dahurica, including imperatorin, isoimperatorin, phellopterin, 5-methoxypsoralen and 8-methoxypsoralen, markedly inhibited melatonin metabolism with Ki values 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. CONCLUSION AND IMPLICATIONS: Coumarins from A. dahurica inhibited melatonin metabolism in vivo and in vitro. Our findings provide vital guidance for the clinical use of melatonin.
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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 Cmax of melatonin in human subjects. Coumarins from A. dahurica, including imperatorin, isoimperatorin, phellopterin, 5-methoxypsoralen and 8-methoxypsoralen, markedly inhibited melatonin metabolism with Ki values 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. CONCLUSION AND IMPLICATIONS: Coumarins from A. dahurica inhibited melatonin metabolism in vivo and in vitro. Our findings provide vital guidance for the clinical use of melatonin.
Authors: Paal Methlie; Eystein E S Husebye; Steinar Hustad; Ernst A Lien; Kristian Løvås Journal: Eur J Endocrinol Date: 2011-09-06 Impact factor: 6.664