Inhibitory Effects of Phyllanthus amarus and Its Major Lignans on Human Microsomal Cytochrome P450 Activities: Evidence for CYP3A4 Mechanism-Based Inhibition

Taesotikul, Theerada; Dumrongsakulchai, Weeraya; Wattanachai, Nitsupa; Navinpipat, Vichien; Somanabandhu, Aimon; Tassaneeyakul, Wongwiwat; Tassaneeyakul, Wichittra

doi:10.2133/dmpk.dmpk-10-rg-107

Cited by 40 publications

(33 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several medicinal herbs, including Allium sativum, Camellia sinensis, Ginkgo biloba, Glycyrrhiza glabra, Coptidis rhizoma, Silybi fructus, and St. John's wort are associated with herb-drug interactions attributable to inhibition and/or induction of drug-metabolizing enzymes [14][15][16][17]. Several lignans including honokiol [18], machilin A [19], magnolol [20], schizandrins [21], schizandrol B [22], phyllantin, hypophyllantin [23], and podophyllotoxin [24] cause herb-drug interactions featuring inhibition of CYP enzymes.…”

Section: Resultsmentioning

confidence: 99%

Inhibitory Effects of Aschantin on Cytochrome P450 and Uridine 5′-diphospho-glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

et al. 2016

View full text Add to dashboard Cite

Abstract:Aschantin is a bioactive neolignan found in Magnolia flos with antiplasmodial, Ca 2+ -antagonistic, platelet activating factor-antagonistic, and chemopreventive activities. We investigated its inhibitory effects on the activities of eight major human cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes of human liver microsomes to determine if mechanistic aschantin-enzyme interactions were evident. Aschantin potently inhibited CYP2C8-mediated amodiaquine N-de-ethylation, CYP2C9-mediated diclofenac 4'-hydroxylation, CYP2C19-mediated [S]-mephenytoin 4'-hydroxylation, and CYP3A4-mediated midazolam 1'-hydroxylation, with K i values of 10.2, 3.7, 5.8, and 12.6 µM, respectively. Aschantin at 100 µM negligibly inhibited CYP1A2-mediated phenacetin O-de-ethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated bupropion hydroxylation, and CYP2D6-mediated bufuralol 1'-hydroxylation. At 200 µM, it weakly inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A6-catalyzed N-acetylserotonin glucuronidation, and UGT1A9-catalyzed mycophenolic acid glucuronidation, with IC 50 values of 131.7, 144.1, and 71.0 µM, respectively, but did not show inhibition against UGT1A3, UGT1A4, or UGT2B7 up to 200 µM. These in vitro results indicate that aschantin should be examined in terms of potential interactions with pharmacokinetic drugs in vivo. It exhibited potent mechanism-based inhibition of CYP2C8, CYP2C9, CYP2C19, and CYP3A4.

show abstract

Section: Resultsmentioning

confidence: 99%

Inhibitory Effects of Aschantin on Cytochrome P450 and Uridine 5′-diphospho-glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

et al. 2016

View full text Add to dashboard Cite

show abstract

“…benzopyran-7-one) furanocumarins from grapefruit, 18) rutaecarpine and limonene from Evodia rutaecarpa, 19) methylenedioxyphenyl lignans from Piper, 20) kaempferol from Zingiber aromaticum, 21) 5-methoxypsoralen from Foeniculum vulgare, 22) and lignans from Phyllanthus amarus, 23) have all been shown to be responsible for MBI of CYP3A4. Moreover, interactions between these compounds and therapeutic drugs could occur in vivo.…”

Section: )mentioning

confidence: 99%

“…[14][15][16] Mechanism-based inhibition (MBI) of CYP3A4 is characterized by nicotinamide adenine dinucleotide phosphate (NADPH)-, time-, and concentration-dependent enzyme inactivation that occurs when some substrates are converted by CYPs into reactive metabolites. 17) Several phytochemicals, including GF-I-1 (4-[ [6-hydroxy-7 [1] benzopyran-7-one) furanocumarins from grapefruit, 18) rutaecarpine and limonene from Evodia rutaecarpa, 19) methylenedioxyphenyl lignans from Piper, 20) kaempferol from Zingiber aromaticum, 21) 5-methoxypsoralen from Foeniculum vulgare, 22) and lignans from Phyllanthus amarus, 23) have all been shown to be responsible for MBI of CYP3A4. Moreover, interactions between these compounds and therapeutic drugs could occur in vivo.…”

mentioning

confidence: 99%

Mechanism-Based Inhibition of Recombinant Human Cytochrome P450 3A4 by Tomato Juice Extract

Sunaga

Ohkawa

Nakamura

et al. 2012

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

This study investigates whether tomato juice can inhibit cytochrome P450 (CYP) 3A4-mediated drug metabolism. Three commercially available, additive-free tomato juices, along with homogenized fresh tomato, were analyzed for their ability to inhibit testosterone 6β-hydroxylation activity using human recombinant CYP3A4. Results were compared to that of grapefruit juice. Ethyl acetate extracts of the tomato juices moderately reduced residual activity of CYP3A4 testosterone 6β-hydroxylation activity by 19.3-26.2% with 0-min preincubation. Residual activity was strongly reduced by 69.9-83.5% at 20-min preincubation, a reduction similar to that of grapefruit juice extract, known to contain constituents of mechanism-based inhibitors. One juice extract (tomato juice C) showed irreversible dose-and preincubation time-dependent and partial nicotinamide adenine dinucleotide phosphate (NADPH)-dependent inhibition of CYP3A4 activity. Furthermore, we examined whether the CYP3A4 inhibitory effect of tomato juice was substrate dependent by examining midazolam 1′-hydroxylation activity and nifedipine oxidation activity, in addition to testosterone 6β-hydroxylation activity. Tomato juice showed a potent inhibitory effect on nifedipine oxidation activity, which was comparable to that on testosterone 6β-hydroxylation activity; however, it showed a weak inhibitory effect on midazolam 1′-hydroxylation activity. We conclude that tomato juice contains one or more mechanism-based and competitive inhibitor(s) of CYP3A4. Additionally, significant CYP3A4 inhibitory activity did not result from lycopene, a major compound in tomato. Although the active compound was uncertain, a strong CYP3A4 inhibitory activity was observed in other solanaceous plants, i.e., potato, eggplant, sweet pepper, and capsicum. Therefore, responsible compounds in tomato are likely commonly shared among solanaceous vegetables.Key words tomato juice; mechanism-based inhibition; food-drug interaction; human recombinant cytochrome P450 3A4 Many foods and/or beverages have recently been found to influence drug metabolism or transport, sometimes resulting in clinically important drug interactions. This food-drug interaction is a critical aspect of pharmacotherapy. Food-drug interaction can be viewed in terms of pharmacokinetics and pharmacodynamics. Pharmacokinetic interactions can involve enzymes and transporters that are implicated in drug absorption, distribution, metabolism, or excretion. Pharmacodynamic interactions involve the pharmacological effect of a drug or physiologic effect of a dietary constituent. 1)Foods that inhibit drug metabolism enzymes, such as cytochrome P450 (CYP), elevate the blood concentration of co-administered drugs, resulting in a food-drug interaction, which sometimes causes adverse effects. [2][3][4] In vitro screening assays with beverages and foods such as beer, red wine, black and herbal tea, garlic, spices, mace, nutmeg, fruits, and fruit juices have all shown the ability to inhibit enzyme-mediated drug metabolism. [5][6][7][8][9][10] CYP...

show abstract

Section: Editorialmentioning

confidence: 99%

“…In this case, the subsequent recovery of P450 enzyme activity is completely reliant on de novo synthesis of new proteins and thereby produces a significant delay between withdrawal of the herbal product and recovery of metabolic activity. Reversible inhibition compared with mechanism based inhibition is characterized by a time, concentration and NADPH dependence [11,12].The induction of CYP450 enzymes by herbal products can also have serious effects on the pharmacokinetics of drugs which could result in increases in drug clearance, bioactivation of prodrugs and in concentration of toxic metabolites. An increase in the clearance of a drug due to higher metabolic activity stemming from the induction of CYP450 enzymes from an herbal product will reduce the therapeutic effect of the drug [5,[13][14][15].…”

mentioning

confidence: 99%

Mechanisms and Implication of Drug-Herbal Interactions

Gorman¹

2012

JBB

View full text Add to dashboard Cite

EditorialIt has been well recognized that an increasing percentage of the population is using herbal products for both preventive and therapeutic purposes. Often times the use of herbals is associated with attenuating side-effects produced from therapeutic drugs such as chemotherapeutic regimen. The basis of this usage of herbal products is the concept that being a natural product, the herbal must be safe to use. However, contrary to this perception it has been well documented that significant pharmacokinetic and/or pharmacodynamic effects can occur through herb-drug interaction [1,2] which has led to an increased concern regarding the safety and even toxicity of the coadministration of these products with therapeutic drugs [3][4][5][6][7]. This effect is exacerbated more so for drugs that have a narrow therapeutic index (e.g., warfarin, digoxin, and many chemotherapeutic agents). The mechanisms of herbal-drug interaction are generally pharmacokinetic in nature and result in changes in absorption and metabolism of the therapeutic agent. In addition to the chemical/physical properties of drugs that effect absorption after oral dosing (e.g., lipid/water solubility, molecular size, degree of ionization, etc), the inhibition or induction of drug transporters can have a substantial effect on the amount of drug absorbed. Perhaps the best characterized drug transporter is P-glycoprotein (P-gp) which has been found in the apical membrane of cells in various organs including the gastrointestinal tract, liver, lungs, and kidneys. Active compounds in the herbal product have been shown to function as transporter substrates resulting in either inhibition or induction of P-gp causing either elevated or reduced drug concentrations, respectively [7,8]. These alterations in drug concentration could result in either a sub-therapeutic level of exposure or potentially produce toxic side effects.Herbal products also have components which function as cytochrome P450 (CYP450) substrates which may also result in the inhibition [9] or induction [10] of the metabolizing enzymes. For inhibition of CYP450 enzymes, herbal products do so in a mixed competitive/noncompetitive manner depending on the particular isozyme and active compounds in the product [9,11]. Competitive inhibition is reversible and is usually simple competition between the drug and the active herbal component for the reactive site on the enzyme. Noncompetitive inhibition is typically characterized by reversible binding of the inhibitor at an allosteric site on the enzyme resulting in a change in its conformation where the drug substrate can still bind but the enzyme cannot catalyze the biotransformation of the drug. Additionally, active components of the herbal may bind irreversibly through covalent interactions with the enzyme thereby reducing the concentration of the enzyme. Alternatively, metabolites of the herbal may also bind irreversibly to the enzyme (mechanism based inhibition) again reducing the pool of enzymes available to catalyze biotransformations of the drug....

show abstract

Inhibitory Effects of Phyllanthus amarus and Its Major Lignans on Human Microsomal Cytochrome P450 Activities: Evidence for CYP3A4 Mechanism-Based Inhibition

Cited by 40 publications

References 31 publications

Inhibitory Effects of Aschantin on Cytochrome P450 and Uridine 5′-diphospho-glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

Inhibitory Effects of Aschantin on Cytochrome P450 and Uridine 5′-diphospho-glucuronosyltransferase Enzyme Activities in Human Liver Microsomes

Mechanism-Based Inhibition of Recombinant Human Cytochrome P450 3A4 by Tomato Juice Extract

Mechanisms and Implication of Drug-Herbal Interactions

Contact Info

Product

Resources

About