**5.11. Papaya (***Carican papaya* **L.)**

Papaya is prized worldwide for its flavor and nutritional properties. An ethno-botanical sur‐ vey showed that papaya is commonly used in traditional medicine for the treatment of vari‐ ous human diseases, including abdominal discomfort, pain, malaria, diabetes, obesity, infections, and oral drug poisoning [111,112]. Papaya leaves and seeds are known to contain proteolytic enzymes (papain, chymopapain), alkaloids (carpain, carpasemine), sulfurous compounds (benzyl iso- thiocyanate), flavonoids, tannins, triterpenes, anthocyanins, organic acids and oils. Papaya fruit is a good source of nutrients and some phytochemicals such as beta-cryptoxanthin and benzyl isothiocyanates [113]. Hidaka et al. found that *papaya* pro‐ duced an inhibition of CYP3A activity in human microsomes [114]. So far, there has been no clinical report suggesting adverse food-drug interaction caused by the intake of papaya. Ac‐ cordingly, the inhibition of CYP3A by papaya may not be observed in vivo. However, the results obtained by others raised the hypothesis that papaya extracts were capable of alter‐ ing the pharmacokinetics of therapeutic drugs coadministered via CYP3A inhibition, as in the case of grapefruit. Thus, the possibility of adverse food-drug interaction involving pa‐ paya and medicine acting via CYP3A metabolism should be examined in vivo. The empiri‐ cal evidence regarding the wide use of fermented papaya preparation (FPP), especially by elderly people, has indicated an unknown collateral effect, i.e., drops in blood sugar levels, especially in the afternoon. Those findings have been corroborated by a clinical study that 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 antidiabetic therapy could suffer from potential drug-food interaction.

### **5.12. Leafy vegetables**

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‐

Apple and its products contain high amounts of polyphenols, which show diverse biological activities and may contribute to beneficial health effects such as protecting the intestine against inflammation due to chronic inflammatory bowel diseases [108, 109]. It has been found that apple juice extract inhibits CYP1A1 at levels of CYP1A1 mRNA, protein, and en‐ zymatic activity [110]. On the other hand, it has also been reported that apple juice and its constituents can interact with members of the OATP transporter family (OATP-1, OATP-3 and NTCP) by reducing their activities *in vitro*. The functional consequence of such an inter‐ action was a significant reduction in the oral bioavailability of fexofenadine in human plas‐ ma levels, possibly by preferential direct inhibition of intestinal OATP activity [29]. These findings suggest that apple might interact with OATP substrates (e.g., estrone-3-sulfate, del‐

Papaya is prized worldwide for its flavor and nutritional properties. An ethno-botanical sur‐ vey showed that papaya is commonly used in traditional medicine for the treatment of vari‐ ous human diseases, including abdominal discomfort, pain, malaria, diabetes, obesity, infections, and oral drug poisoning [111,112]. Papaya leaves and seeds are known to contain proteolytic enzymes (papain, chymopapain), alkaloids (carpain, carpasemine), sulfurous compounds (benzyl iso- thiocyanate), flavonoids, tannins, triterpenes, anthocyanins, organic acids and oils. Papaya fruit is a good source of nutrients and some phytochemicals such as beta-cryptoxanthin and benzyl isothiocyanates [113]. Hidaka et al. found that *papaya* pro‐ duced an inhibition of CYP3A activity in human microsomes [114]. So far, there has been no clinical report suggesting adverse food-drug interaction caused by the intake of papaya. Ac‐ cordingly, the inhibition of CYP3A by papaya may not be observed in vivo. However, the results obtained by others raised the hypothesis that papaya extracts were capable of alter‐ ing the pharmacokinetics of therapeutic drugs coadministered via CYP3A inhibition, as in the case of grapefruit. Thus, the possibility of adverse food-drug interaction involving pa‐ paya and medicine acting via CYP3A metabolism should be examined in vivo. The empiri‐ cal evidence regarding the wide use of fermented papaya preparation (FPP), especially by elderly people, has indicated an unknown collateral effect, i.e., drops in blood sugar levels, especially in the afternoon. Those findings have been corroborated by a clinical study that

tivity by fruit juices is clinically relevant.

torphin II, fexofenadine, vasopressin, and rosuvastatin).

**5.10. Apple (***Malus domestica***)**

14 Drug Discovery

**5.11. Papaya (***Carican papaya* **L.)**

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 pharmacological and toxicological implications in humans.

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 inducing changes in the bioavailability of some drugs.

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‐ trient-drug interactions.

ing that the fruit inhibited the effect of warfarin. They, however, did not establish the cause

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

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

17

Red pepper (*Capsicum annuum* L.) is used as a spice that enhances the palatability of food and drugs such as the counterirritant present in stomach medicines across many countries [151]. The pungencyof red pepper is derived from a group of compounds called capsaici‐ noids, which possess an array of biological properties and give it its spicy flavor. Two major capsaicinoids, dihydrocapsaicin (DHC) and capsaicin (CAP) are responsible for up to 90% of the total pungency of pepper fruits. Red pepper has several uses as a fruit stimulant and ru‐ bifacient in traditional medicine; it is also used in the treatment of some diseases such as scarlatina, putrid sore throat, hoarseness, dispepsia, yellow fever, piles and snakebite [152]. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a fundamental component of *Capsicum* fruits. Capsaicin is known to have antioxidant properties and has therefore been associated with potent antimutagenic and anticarcinogenic activities [153]. Early studies have reported that capsaicin strongly inhibited the constitutive enzymes CYP 2A2, 3A1, 2C11, 2B1, 2B2 and 2C6 [154]. There is also a report indicating that capsaicin is a substrate of CYP1A2 [155]. Pharmacokinetic studies in animals have shown that a single dose of *Capsicum* fruit could affect the pharmacokinetic parameters of theophylline, while a repeated dose affected the metabolic pathway of xanthine oxidase [156]. Therefore, a potential interaction may occur when is taken along with some medicines that are CYP450 substrates. Recently, it has been evidenced that red pepper induces alterations in intestinal brush border fluidity and passive permeability properties associated with the induction of increased microvilli length and pe‐ rimeter, resulting in an increased absorptive surface for the small intestine and an increased bioavailability not only of micronutrients but also of drugs [157]. Cruz et al. have shown that pepper ingestion reduces oral salicylate bioavailability, a likely result of the gastrointes‐ tinal effects of capsaicin [158]. On the other hand, Imaizumi et al. have reported capsaici‐ noid-induced changes of glucose in rats. Therefore, there is a possible interaction risk between red pepper and hypoglycemic drugs in diabetic patients [159]. Patients consuming red pepper and taking antidiabetic therapy could suffer potential drug-food interaction.

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 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,

vegetables were responsible for the inhibitory effects on CYP1A2 ^115 [117,160].

of such inhibition [149, 150].

**5.14. Other vegetables**
