**5.9. Raspberry (***Rubus* **spp.)**

Berries have been shown to have a positive impact on several chronic conditions including obesity, cancer, and cardiovascular and neurodegenerative diseases [102-104]. Like other fruits, raspberries contain micro- and macronutrients such as vitamins, minerals, and fiber. Their biological properties, however, have been largely attributed to high levels of various phenolic compounds, as well as the interactive synergies among their natural phytochemical components (e.g., ellagic acid, quercetin, gallic acid, anthocyanins, cyanidins, pelargonidins, catechins, kaempferol and salicylic acid). Raspberry or raspberry constituents have antioxi‐ dant and anti-inflammatory properties, and inhibit cancer cell growth [105-107]. Black rasp‐ berries (*Rubus coreanus)* have been called the "king of berries" for their superior health benefits, whereas black mulberry (*Morus nigra)* is most commonly used for its antioxidants properties and for its high bioactive content of phenolics, anthocyanins, and gallic acid. It has been shown that black raspberry and black mulberry are able to inhibit the human CYP3A-catalyzed midazolam 1-hydroxylation activity in liver microsomes, and the inhibito‐ ry effects are somewhat greater than those of pomegranate [49, 56]. It has also been reported that black mulberry extract potently inhibits OATP-B function at concentrations that seem to be physiologically relevant *in vitro* [53]*.* These results suggest that black raspberry and black mulberry may decrease the plasma concentrations of concomitantly ingested OATP-B sub‐ strate drugs or increase the plasma concentration levels of concomitantly ingested CYP3Asubstrate drugs. *In vivo* studies on the interaction between black mulberry and black raspberry and CYP3A substrates are needed to determine whether inhibition of CYP3A ac‐ tivity by fruit juices is clinically relevant.

shows that FPP use can induce a significant decrease in plasma sugar levels in both healthy subjects and type 2 diabetic patients [115]. Therefore, patients consuming papaya and taking

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

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

15

Broccoli (*Brassica oleracea var. italica)* and cauliflower (*Brassica oleracea var. botrytis)* are unique among the common cruciferous vegetables that contain high levels of the aliphatics glucosi‐ nolate and glucoraphanin [116]. Upon hydrolysis, glucoraphanin produces several products that include the bioactive isothiocyanate sulforaphane. The percentage of isothiocyanate sul‐ foraphane present in these vegetables may vary depending on conditions of hydrolysis, food handling, and preparation procedures [117, 118]. In animal studies, dietary freezedried broccoli was found to offer protection against several cancers [119]. However, brocco‐ li, cauliflower and their glucosinolate hydrolysis products have been shown to induce phase I and phase II drug-metabolizing enzymes in intact liver cells from both rats and humans. The isothiocyanate sulforaphane decreased the enzyme activities hepatocytes associated with CYP1A1 and 2B1/2, namely ethoxyresorufin-O-deethylase and pentoxyresorufin-Odealkylase, respectively, in a dose-dependent manner [120]. An increase in hGSTA1/2 mRNA has been observed in isothiocyanate sulforaphane-treated human hepatocytes, whereas the expression of CYP3A4, the major CYP in the human liver, markedly decreased at both mRNA and activity levels [121]. Conversely, it was recently shown that sulforaphane induces mRNA levels of MRP1 and MRP2 in primary hepatocytes and Caco-2 cells [122]. It has been additionally reported that broccoli is able to induce the activity of phenolsulfo‐ transferases [123]. These results suggest that other vegetables with a high content of isothio‐ cyanates, such as those of the family *Cruciferae* (e.g., cabbage, cauliflower, Brussels sprouts, watercress, broccoli, and kale) and the genus *Raphanus* (radishes and daikons) may have

Watercress is another important member of the cruciferous vegetables, an excellent source for glucosinolates and other bioactive phytochemicals [124]. Watercress (*Nasturtium offici‐ nale)* is an exceptionally rich dietary source of beta-phenylethyl isothiocyanate (PEITC) [125]. Previous studies have shown that a single ingestion of watercress inhibits the hydrox‐ ylation of chlorzoxazone, an *in vivo* probe for CYP2E1, in healthy volunteers [126]. It has al‐ so been shown that watercress is a bifunctional agent with the ability to induce both phase I (CYP450) and II enzymes. Adding watercress juice to human liver cells induced the activity of CYP4501A and ethoxyresorufin-O-deethylase and NAD(P)H-quinone reductase [127]. Ac‐ cording to reports, PEITC also has several anti-carcinogenic effects given that it can inhibit phase I enzymes and/or activate phase II enzymes. Watercress juice can increase the en‐ zymes *SOD* and *GPX* in blood cells *in vitro* and *in vivo* [128]. Isothiocyanates also interact with ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein, MRP1, MRP2 and BCRP, and may influence the pharmacokinetics of substrates of these transporters [26]. According to current data, watercress and isothiocyanate may have clinical repercussions by

antidiabetic therapy could suffer from potential drug-food interaction.

pharmacological and toxicological implications in humans.

inducing changes in the bioavailability of some drugs.

**5.12. Leafy vegetables**
