**5.14. Other vegetables**

Spinach (*Spinacia oleracea)* is an important antioxidant vegetable usually consumed after boiling the fresh or frozen leaves [129]. Freshly cut spinach leaves contain approximately 1,000 mg of total flavonoids per kilogram, and the occurrence of at least 10 flavonoid glyco‐ sides has been reported [130]. These are glucuronides and acylated di-and triglycosides of methylated and methylene dioxide derivatives of 6-oxygenated flavonols [131]. While epide‐ miological and preclinical data support the nutritional benefits of spinach and the safety of its consumption there are no publications about its effects on drug metabolizing enzymes and drug transporters. Little is currently known about the *in vivo* effects these compounds have on the bioavailability of xenobiotics the clearance and/or tissue distribution of which is determined by active transport and biotransformation. Platt and others [132] reported the protective effect of spinach against the genotoxic effects of 2-amino-3-methylimidazo[4,5 f]quinoline (IQ) by interaction with CYP1A2 as a mechanism of anti-genotoxicity. Its high isothiocyanate and flavonoid content demands additional research to evaluate possible nu‐

Tomatoes (*Lycopersicon esculentum)* and tomato-based products are a source of important nu‐ trients and contain numerous phytochemicals, such as carotenoids, that may influence health (carotenoids such as phytofluene, phytoene, neurosporene, γ-carotene, and ζ-caro‐ tene) [133,134]. Tomatoes are also a source of a vast array of flavonols (e.g., quercetin and kaempferol), phytosterols, and phenylpropanoids [135]. Lycopene is the most important car‐ otenoid present in tomatoes and tomato products, and their dietary intake has been linked to a decreased risk of chronic illnesses such as cancer and cardiovascular disease [136,137]. Studies performed on human recombinant CYP1 showed that lycopene inhibits CYP1A1 and CYP1B1. Lycopene has also been shown to slightly reduce the induction of ethoxyresor‐ ufin-*O*-deethylase activity by 20% by DMBA in MCF-7 cells [138]. It appears to inhibit bioac‐ tivation enzymes and induce detoxifying enzymes. It has been suggested that lycopene might have a potential advantage over other phytochemicals by facilitating the elimination of genotoxic chemicals and their metabolites [138]. Recent *in vitro* evidence suggests that high dose lycopene supplementation increases hepatic cytochrome P4502E1 protein and in‐

Carrots (*Daucus carrota)* are widely consumed as food. The active components of carrots, which include beta-carotene and panaxynol have been studied by many researchers [140-142]. Carrots induce phenolsulfotransferase activity [123] and decrease CYP1A2 activity [122]. It has been reported that a carrot diet increased the activity of ethoxycoumarin O-dee‐

Avocado (*Persea americana*) is a good source of bioactive compounds such as monounsatu‐ rated fatty acids and sterols [144]. Growing evidence on the health benefits of avocadoes have led to increased consumption and research on potential health benefits [145, 146]. Phy‐ tochemicals extracted from avocado can selectively induce several biological functions [147,148]. Two papers published in the 1990's reported avocados interact with warfarin, stat‐

trient-drug interactions.

16 Drug Discovery

**5.13. Vegetable fruits**

flammation in alcohol-fed rats [139].

thylase ECD activity in a mouse model [143].

Yeh and Yen have reported that asparagus, cauliflower, celery and eggplant induced signifi‐ cant phenol sulfotransferase –P (PST-P) activity, whereas asparagus, eggplant and potato in‐ duced PST-M activity [123]. It has been have also reported that a diet supplemented with apiaceous vegetables (dill weed, celery, parsley, parsnip) resulted in a 13-15% decrease in CYP1A2 activity [122]. The authors speculate that furanocumarins present in the apiaceous vegetables were responsible for the inhibitory effects on CYP1A2 ^115 [117,160].

Vegetables such as cabbage, celery, onion and parsley are known to have a high content of polyphenols. It has been reported that polyphenols can potentially affect phase I metabolism either by direct inhibition of phase I enzymes or by regulating the expression of enzyme lev‐ els *via* their interactions with regulatory cascades. Several studies have directly and indirect‐ ly shown that dietary polyphenols can modulate phase II metabolism [161]. In addition, polyphenols have been shown to interact with ABC drug transporters involved in drug re‐ sistance and drug absorption, distribution and excretion [32].

gut in correct amounts. The overall health benefits of polyphenols are uncertain, and con‐ sumption of large quantities of them in fortified foods or supplements should not yet be

Fruit/Vegetable-Drug Interactions: Effects on Drug Metabolizing Enzymes and Drug Transporters

http://dx.doi.org/10.5772/48283

19

Flavonoids have been known as plant pigments for over a century and belong to a vast group of phenolic compounds that are widely distributed in all foods of plant origin. Un‐ fortunately, the potentially toxic effects of excessive flavonoid intake are largely ignored. At higher doses, flavonoids may act as mutagens, pro-oxidants that generate free radicals, and as inhibitors of key enzymes involved in hormone metabolism [171]. It has been shown that phenol ring-containing flavonoids yield cytotoxic phenoxyl radicals upon oxidation by per‐ oxidases; co-oxidize unsaturated lipids, GSH, NADH, ascorbate, and nucleic acids; and cause ROS formation and mitochondrial toxicity [172]. In high doses, the adverse effects of flavonoids may outweigh their beneficial ones, and caution should be exercised when in‐ gesting them at levels above those which would be obtained from a typical vegetarian diet [173]. Moreover, it is possible that people ingesting a vegetarian or Mediterranean diet may

Inhibition of CYP enzymes, which are necessary for carcinogen activation, is a beneficial chemopreventive property of various flavonoids but may be a potential toxic property in flavonoid-drug interactions. Inhibition of CYP activities by flavonoids has been extensively studied because of their potential use as blocking agents during the initial stage of carcino‐ genesis [174]. The general conclusion after an analysis of available data on CYP-flavonoid interactions is that flavonoids possessing hydroxyl groups inhibit CYP activity, whereas those lacking hydroxyl groups may induce the metabolizing enzyme [175]. Flavonoids can either inhibit or induce human CYP enzymes depending on their structure, concentration, or experimental conditions [176]. The interaction of flavonoids with CYP3A4, the predominant human hepatic and intestinal CYP responsible for metabolizing 50% of therapeutic agents as

The simultaneous administration of flavonoids present in fruits or vegetables and clinically used drugs may cause flavonoid-drug interactions by modulating the pharmacokinetics of certain drugs, which results in an increase in their toxicity or a decline in their therapeutic effect, depending on the flavonoid structure [178]. Additional reasons for concern regarding mega flavonoid supplements include potential flavonoid-drug interactions, since flavonoids have been shown to both induce and inhibit drug-metabolizing enzymes [38, 39]. Further re‐ search regarding the potential toxicities associated with flavonoids and other dietary phe‐

It is a fact that diets based on fruits and vegetables may have a variety of phytochemicals, as was mentioned earlier, so the possibility of developing a drug-food interaction is high. While dietary polyphenols may be beneficial in the correct amount, but too much may not

be taking medication and thus have drug-food interaction.

well as the activation of some carcinogens, is of particular interest [177].

nolics is required if these plant-derived products are to be used as therapy.

be good and combining them with medication should be avoided.

encouraged [170].
