Flavonoids diosmetin and luteolin inhibit midazolam metabolism by human liver microsomes and recombinant CYP 3A4 and CYP3A5 enzymes

Quintieri, Luigi; Palatini, Pietro; Nassi, Alberto; Ruzza, Paolo; Floreani, Maura

doi:10.1016/j.bcp.2007.11.012

Cited by 86 publications

(55 citation statements)

References 37 publications

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“…However, CYP3A4 was found to be expressed in all adult livers [21] and to be the predominant CYP3A expressed in human enterocytes, indicating that the contribution of CYP3A5 to midazolam 1-hydroxylation is small [22,23] . In spite of the high similarity (84% of identity in amino acid sequence) and substantial overlap of substrate specificities [3,24] , the CYP3A4 and CYP3A5 proteins have been shown to possess different enzymatic properties, including susceptibility to inhibitors. A previous study showed that the catalytic activity of CYP3A5 was less than that of CYP3A4.…”

Section: Discussionmentioning

confidence: 99%

“…CYP3A4 accounts for roughly 40% of the total cytochrome P450 in human liver microsomes, and metabolizes more than 50% of the clinically used drugs. CYP3A4 is also expressed in the small intestine, where it contributes to the first-pass elimination of many drugs [1][2][3][4] . The ability of CYP3A4 to metabolize numerous structurally unrelated compounds accounts for the large number of documented drug interactions associated with CYP3A4 inhibition.…”

Section: Introductionmentioning

confidence: 99%

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Bufalin inhibits CYP3A4 activity in vitro and in vivo

Zhang

et al. 2009

Acta Pharmacol Sin

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Aim:To investigate the inhibitory interactions of bufalin and CYP3A4. Methods: Recombinant human CYP3A4 was incubated with bufalin in vitro. Bufalin was administered ig and iv to Wistar rats to further estimate its impact on CYP3A4, and midazolam was given to index the activity of CYP3A4. Results: The IC 50 of bufalin was 14.52 μmol/L. Bufalin affected CYP3A4 activity with increases in AUC 0-t and t 1/2 , and decreases in CL and the formation of 1-hydroxy-midazolam after ig or iv administration of midazolam (P<0.05). An increase in C max after ig bufalin administration (P<0.05) was observed. Conclusion: Bufalin showed a modest but significant inhibition of CYP3A4 both in vitro and in vivo. The likelihood of an interaction between bufalin and the CYP3A4-metabolized drugs in human might not be negated.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bufalin inhibits CYP3A4 activity in vitro and in vivo

Zhang

et al. 2009

Acta Pharmacol Sin

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“…For example, the catechins from green tea, the organosulphur compounds such as diallyl sulphide from garlic, galangin found in honey, sylimarin from milk thistle and other flavonoids, such as diosmetin and luteolin, have all been reported to be inhibitors of various CYPs [7,65,67,95]. There is limited evidence to demonstrate that such in vitro interactions translate to significant in vivo interactions in humans.…”

Section: Inhibition Of Phases 1 and 2 Enzymes By Polyphenolsmentioning

confidence: 99%

Improving the oral bioavailability of beneficial polyphenols through designed synergies

2009

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“…However, it has been recently reported that several flavonoids, such as kaempferol, quercetin, naringenin, apigenin, myricetin, chrysin, diosmetin, and luteolin, inhibit the catalytic activity of CYP3A4. [38][39][40] Furthermore, naringenin, apigenin, luteolin, kaempferol, myricetin, and quercetin are the major flavonoid components found in tomato. 41) Flavonoids, which are also major constituents of grapefruit juice, are not known to be mechanism-based inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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

Sunaga

Ohkawa

Nakamura

et al. 2012

Biological & Pharmaceutical Bulletin

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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...

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Flavonoids diosmetin and luteolin inhibit midazolam metabolism by human liver microsomes and recombinant CYP 3A4 and CYP3A5 enzymes

Cited by 86 publications

References 37 publications

Bufalin inhibits CYP3A4 activity in vitro and in vivo

Bufalin inhibits CYP3A4 activity in vitro and in vivo

Improving the oral bioavailability of beneficial polyphenols through designed synergies

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

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