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Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies.

Qiu JX, Zhou ZW, He ZX, Zhang X, Zhou SF, Zhu S - Drug Des Devel Ther (2015)

Bottom Line: The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes.The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans.Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response.

View Article: PubMed Central - PubMed

Affiliation: Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China ; Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.

ABSTRACT
Ginger is one of the most commonly used herbal medicines for the treatment of numerous ailments and improvement of body functions. It may be used in combination with prescribed drugs. The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes. This study aimed to determine the molecular interactions between 12 main active ginger components (6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, ar-curcumene, β-bisabolene, β-sesquiphelandrene, 6-gingerdione, (-)-zingiberene, and methyl-6-isogingerol) and human cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 and to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the 12 ginger components using computational approaches and comprehensive literature search. Docking studies showed that ginger components interacted with a panel of amino acids in the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π-π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki ] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans. Moreover, ginger components showed a rapid half-life and no to low toxicity in humans. Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response. More studies are warranted to identify and confirm potential ginger-drug interactions and explore possible interactions of ginger with human CYPs and other functionally important proteins, to reduce and avoid side effects induced by unfavorable ginger-drug interactions.

No MeSH data available.


Related in: MedlinePlus

Binding modes of main active components of ginger in human CYP2C19 (PDB code 4GQS).Notes: Each compound–CYP2C19 complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected. (A) 6-Gingerol; (B) 8-gingerol; (C) 10-gingerol; (D) 6-shogaol; (E) 8-shogaol; (F) 10-shogaol; (G) ar-curcumene; (H) β-bisabolene; (I) β-sesquiphelandrene; (J) 6-gingerdione; (K) (−)-zingiberene; and (L) methyl-6-isogingerol.Abbreviation: CYP, cytochrome P450.
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f4-dddt-9-841: Binding modes of main active components of ginger in human CYP2C19 (PDB code 4GQS).Notes: Each compound–CYP2C19 complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected. (A) 6-Gingerol; (B) 8-gingerol; (C) 10-gingerol; (D) 6-shogaol; (E) 8-shogaol; (F) 10-shogaol; (G) ar-curcumene; (H) β-bisabolene; (I) β-sesquiphelandrene; (J) 6-gingerdione; (K) (−)-zingiberene; and (L) methyl-6-isogingerol.Abbreviation: CYP, cytochrome P450.

Mentions: Based on our docking studies, we identified the interactions between amino acid residues in the CYP active sites and ginger components (Table 1). Most interactions occurred in the active site of CYP2D6 (Figure 5A–L), and, to a lesser extent, in the active sites of CYP3A4 (Figure 6A–L), 2C9 (Figure 3A–L), 1A2 (Figure 2A–L), and 2C19 (Figure 4A–L). It suggests that CYP2D6 may be the most favorable enzyme for ginger components. Indeed, CYP2D6 is known to detoxify the toxic xenobiotics in plants.21 H-bond formation was the main interaction between ginger components and CYPs (Table 1). The hydroxyl- and keto-groups were two major reaction sites for the ginger–CYP interactions. The most involved amino acids were Arg and Asn. Arg101, Arg441, and His376 were the most important amino acid residues accounting for the interaction between ginger compounds and CYP2D6 active site. Asn204, Asn217, Asn218, Gly296, and Gln214 were involved in the interaction in the active site of CYPC19. There were only five ginger compounds interacting with the active site of CYP2C19, which is the least among the five CYPs. Gly316, Phe226, and Phe260 were responsible for the interaction between ginger compounds and CYP1A2 active site. Thr301 and Leu208 were the most important residues in the active site of CYP2C9 and Asn107 and Asp293 played a lesser important role. For CYP3A4, Ala305 and Glu374 were the most important residues responsible for the interaction in the active site. π–π stacking only occurred between CYP1A2 and 6-shogaol, 8-shogaol, 6-gingerdione, and methyl-6-isogingerol at Phe226 and Phe260 (Table 1). Taken together, the in silico data show that ginger components interact with human CYPs, suggesting that the 12 ginger components may act as ligands for CYP1A2, 2C9, 2C19, CYP2D6, and 3A4 and that the interactions between ginger components and CYPs may influence the activity of CYPs with a consequence of inhibition in vivo.


Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies.

Qiu JX, Zhou ZW, He ZX, Zhang X, Zhou SF, Zhu S - Drug Des Devel Ther (2015)

Binding modes of main active components of ginger in human CYP2C19 (PDB code 4GQS).Notes: Each compound–CYP2C19 complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected. (A) 6-Gingerol; (B) 8-gingerol; (C) 10-gingerol; (D) 6-shogaol; (E) 8-shogaol; (F) 10-shogaol; (G) ar-curcumene; (H) β-bisabolene; (I) β-sesquiphelandrene; (J) 6-gingerdione; (K) (−)-zingiberene; and (L) methyl-6-isogingerol.Abbreviation: CYP, cytochrome P450.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4338259&req=5

f4-dddt-9-841: Binding modes of main active components of ginger in human CYP2C19 (PDB code 4GQS).Notes: Each compound–CYP2C19 complex with the lowest CDOCKER interaction energy was selected and the 2D and 3D pictures of them were collected. (A) 6-Gingerol; (B) 8-gingerol; (C) 10-gingerol; (D) 6-shogaol; (E) 8-shogaol; (F) 10-shogaol; (G) ar-curcumene; (H) β-bisabolene; (I) β-sesquiphelandrene; (J) 6-gingerdione; (K) (−)-zingiberene; and (L) methyl-6-isogingerol.Abbreviation: CYP, cytochrome P450.
Mentions: Based on our docking studies, we identified the interactions between amino acid residues in the CYP active sites and ginger components (Table 1). Most interactions occurred in the active site of CYP2D6 (Figure 5A–L), and, to a lesser extent, in the active sites of CYP3A4 (Figure 6A–L), 2C9 (Figure 3A–L), 1A2 (Figure 2A–L), and 2C19 (Figure 4A–L). It suggests that CYP2D6 may be the most favorable enzyme for ginger components. Indeed, CYP2D6 is known to detoxify the toxic xenobiotics in plants.21 H-bond formation was the main interaction between ginger components and CYPs (Table 1). The hydroxyl- and keto-groups were two major reaction sites for the ginger–CYP interactions. The most involved amino acids were Arg and Asn. Arg101, Arg441, and His376 were the most important amino acid residues accounting for the interaction between ginger compounds and CYP2D6 active site. Asn204, Asn217, Asn218, Gly296, and Gln214 were involved in the interaction in the active site of CYPC19. There were only five ginger compounds interacting with the active site of CYP2C19, which is the least among the five CYPs. Gly316, Phe226, and Phe260 were responsible for the interaction between ginger compounds and CYP1A2 active site. Thr301 and Leu208 were the most important residues in the active site of CYP2C9 and Asn107 and Asp293 played a lesser important role. For CYP3A4, Ala305 and Glu374 were the most important residues responsible for the interaction in the active site. π–π stacking only occurred between CYP1A2 and 6-shogaol, 8-shogaol, 6-gingerdione, and methyl-6-isogingerol at Phe226 and Phe260 (Table 1). Taken together, the in silico data show that ginger components interact with human CYPs, suggesting that the 12 ginger components may act as ligands for CYP1A2, 2C9, 2C19, CYP2D6, and 3A4 and that the interactions between ginger components and CYPs may influence the activity of CYPs with a consequence of inhibition in vivo.

Bottom Line: The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes.The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans.Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response.

View Article: PubMed Central - PubMed

Affiliation: Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China ; Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.

ABSTRACT
Ginger is one of the most commonly used herbal medicines for the treatment of numerous ailments and improvement of body functions. It may be used in combination with prescribed drugs. The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes. This study aimed to determine the molecular interactions between 12 main active ginger components (6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, ar-curcumene, β-bisabolene, β-sesquiphelandrene, 6-gingerdione, (-)-zingiberene, and methyl-6-isogingerol) and human cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 and to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the 12 ginger components using computational approaches and comprehensive literature search. Docking studies showed that ginger components interacted with a panel of amino acids in the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π-π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki ] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans. Moreover, ginger components showed a rapid half-life and no to low toxicity in humans. Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response. More studies are warranted to identify and confirm potential ginger-drug interactions and explore possible interactions of ginger with human CYPs and other functionally important proteins, to reduce and avoid side effects induced by unfavorable ginger-drug interactions.

No MeSH data available.


Related in: MedlinePlus