Flavonoids inhibit genetic toxicity produced by carcinogens in cells expressing CYP1A2 and CYP1A1

Lautraite, S.

doi:10.1093/mutage/17.1.45

Cited by 74 publications

(41 citation statements)

References 50 publications

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“…There is accumulating evidence on cancer chemopreventive properties of flavonoids from experiments with in vitro models such as recombinant CYPs and hepatic microsomes Lautraite et al, 2002;Lee et al, 2001;Ueng et al, 2001). Flavonoids are thought to be involved in the prevention of a malignancy by reduction of carcinogen formation, with the inhibition of Phase I enzymes, such as members of CYP1 family, probably playing the most important role.…”

Section: B Association Of Herb -Cyp Interactions With Chemoprotectivmentioning

confidence: 99%

Interactions of Herbs with Cytochrome P450

Zhou

Gao²,

Jiang

et al. 2003

Drug Metabolism Reviews

357

207

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A resurgence in the use of medical herbs in the Western world, and the co-use of modern and traditional therapies is becoming more common. Thus there is the potential for both pharmacokinetic and pharmacodynamic herb-drug interactions. For example, systems such as the cytochrome P450 (CYP) may be particularly vulnerable to modulation by the multiple active constituents of herbs, as it is well known that the CYPs are subject to induction and inhibition by exposure to a wide variety of xenobiotics. Using in vitro, in silico, and in vivo approaches, many herbs and natural compounds isolated from herbs have been identified as substrates, inhibitors, and/or inducers of various CYP enzymes. For example, St. John's wort is a potent inducer of CYP3A4, which is mediated by activating the orphan pregnane X receptor. It also contains ingredients that inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Many other common medicinal herbs also exhibited inducing or inhibiting effects on the CYP system, with the latter being competitive, noncompetitive, or mechanism-based. It appears that the regulation of CYPs by herbal products is complex, depending on the herb type, their administration dose and route, the target organ and species. Due to the difficulties in identifying the active constituents responsible for the modulation of CYP enzymes, prediction of herb -drug metabolic interactions is difficult. However, herb-CYP interactions may have important clinical and toxicological consequences. For example, induction of CYP3A4 by St. John's wort may partly provide an explanation for the enhanced plasma clearance of a number of drugs, such as cyclosporine and innadivir, which are known substrates of CYP3A4, although other mechanisms including modulation of gastric absorption and drug transporters cannot be ruled out. In contrast, many organosulfur compounds, such as diallyl sulfide from garlic, are potent inhibitors of CYP2E1; this may provide an explanation for garlic's chemoproventive effects, as many mutagens require activation by CYP2E1. Therefore, known or potential herb -CYP interactions exist, and further studies on their clinical and toxicological roles are warranted. Given that increasing numbers of people are exposed to a number of herbal preparations that contain many constituents with potential of CYP modulation, high-throughput screening assays should be developed to explore herb-CYP interactions.Key Words: Herb; Cytochrome P450; Drug interactions.Abbreviations: Ah, aryl hydrocarbon; AUC, the area of the plasma concentrationtime curve; B[a]P, benzo[a]pyrene; C max , the maximum plasma concentration; CL int , intrinsic clearance; CYP, cytochrome P450; DAD, diallyl disulfide; DAS, diallyl sulfide; DASO, diallyl sulfoxide; DASO 2 , diallyl sulfone; DPS, dipropyl sulfide; DPDS, dipropyl disulfide; K i , inhibition constant; K m , Michaelis -Menten constant; NADPH, nicotinamide adenine dinucleotide phosphate; NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; N-PiP, N-nitrosopiperidine; PgP, P-glycoprotein; PhIP...

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Section: B Association Of Herb -Cyp Interactions With Chemoprotectivmentioning

confidence: 99%

Interactions of Herbs with Cytochrome P450

Zhou

Gao²,

Jiang

et al. 2003

Drug Metabolism Reviews

357

207

View full text Add to dashboard Cite

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“…Epidemiological and laboratory results suggest protective effects of dietary antioxidants from vegetables and vitamin supplements [2]. Recent studies have documented the inhibitory effect of flavinoids and vitamins on genotoxicity of xenobiotic chemicals at the cellular level [3].…”

Section: Introductionmentioning

confidence: 99%

“…However, causal mechanisms of the observed effects are often unclear [4]. In some cases, inhibition has been suggested to occur at the level of enzyme bioactivation [2], while other studies simply document the effect. At molecular and cellular levels, antioxidants can deactivate reactive oxygen species (ROS) [5], which are known to react with DNA [6 -8].…”

Section: Introductionmentioning

confidence: 99%

Studies of DNA Damage Inhibition by Dietary Antioxidants Using Metallopolyion/DNA Sensors

Rusling

2006

Electroanalysis

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Voltammetric sensors featuring thin-films containing osmium and ruthenium metallopolymers were evaluated to monitor the influence of antioxidants on DNA damage reactions. In the first example, apigenin, chrysin, and ascorbic acid were shown to inhibit oxidation of DNA by hydroxyl radicals generated with Fentons reagent. A second example involved films of DNA with myoglobin (Mb) as an enzyme mimic which was used to convert styrene to styrene oxide. Here, the Ru peak of the sensor served as a marker of DNA damage from adduct formation between nucleobases and styrene oxide. There was no influence of the antioxidants on the reaction of styrene oxide itself with DNA films, but significant damage protection was afforded by micromolar amounts of antioxidants when styrene oxide was generated by Mb in the sensor films. This suggests that protection ensued from action of the antioxidants at the enzyme conversion level, probably by reduction of the active ferryloxy intermediate of the protein. Results demonstrate the usefulness of the thin metallopolyion/DNA film sensors in investigations of DNA damage inhibition.

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“…Inhibitors such as dietary flavonoids can block the production of reactive metabolites and thus DNA damage. For example, the flavone acacetin can inhibit CYP1A1-mediated 7-ethoxyresorufin O-dealkylation with an IC 50 of 80 nM (20), and the flavone apigenin can eliminate detectable DNA adduct formation by CYP1A1 activation of benzo [a]pyrene (21). In contrast, in certain malignancies that overexpress CYP1A1, another therapeutic approach utilizes this enzyme to activate anticancer prodrugs to reactive electrophilic species that inhibit tumor growth (22,23).…”

mentioning

confidence: 99%

Human Cytochrome P450 1A1 Structure and Utility in Understanding Drug and Xenobiotic Metabolism

Walsh

Szklarz

Scott

2013

Journal of Biological Chemistry

245

243

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Background: Human cytochrome P450 1A1 (CYP1A1) activates procarcinogens, but the basis of their binding is unknown. Results: A 2.6 Å structure with the inhibitor ␣-naphthoflavone and docking simulations suggest key active site features. Conclusion: CYP1A1 has a planar active site that restricts ligand orientations.Significance: This provides a useful framework for understanding CYP1A1 interactions with a variety of substrates and inhibitors.

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Flavonoids inhibit genetic toxicity produced by carcinogens in cells expressing CYP1A2 and CYP1A1

Cited by 74 publications

References 50 publications

Interactions of Herbs with Cytochrome P450

Interactions of Herbs with Cytochrome P450

Studies of DNA Damage Inhibition by Dietary Antioxidants Using Metallopolyion/DNA Sensors

Human Cytochrome P450 1A1 Structure and Utility in Understanding Drug and Xenobiotic Metabolism

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