Extending the good diet, good health paradigm: modulation of breast cancer resistance protein (BCRP) by flavonoids.

Flavonoids, important constituents of the human diet, are found in a variety of fruits, vegetables, and beverages including wine and teas. As a class, flavonoids are recognized to have numerous biological activities, and a healthy diet rich in fruit and vegetables is linked directly to a reduced risk of cancer (Lee et al., 1991; Middleton et al., 2000) or coronary heart disease (Hertog et al., 1993; Kelly, 2001). With increasing recognition of the potential long-term benefits of these components, they are also being used more frequently as dietary supplements. The biological effects ascribed to the anticancer actions of flavonoids are diverse and include their ability to modulate (1) signal transduction pathways involved in cell proliferation and angiogenesis, (2) enzymes required for metabolic activation of procarcinogens and the detoxification of carcinogens, (3) enzymes involved in estrogen biosynthesis, and (4) potent antioxidant activities (Morris and Zhang, 2006). Recently, drug efflux transporters such as P-glycoprotein (PgpABCB1) and breast cancer resistance protein (BCRP/ ABCG2) were found to transport a range of flavonoids and other nonnutritive food compounds. In this issue, Ebert et al. (2006) report for the first time that these phytochemicals modulate BCRP at the transcriptional level, most likely acting through the aryl hydrocarbon receptor (AhR) pathway. The authors also properly connect the two critical aspects of induction and function by showing that phytochemicals can induce BCRP and link this induction to the observation that phase II metabolites of the widely recognized carcinogen, benzo[a]pyrene (BP), are substrates of BCRP. These data also provide yet another example of the central role of xenobiotic transporters in regulating the disposition and subsequent toxicity of xenobiotics. Specifically, phytochemicals might protect against BP-related cancer by inducing the expression of BCRP and ultimately, decreasing exposure BP and its promutagenic metabolites. The regulation of the enzymes and transporters that contribute to xenobiotic disposition has been extensively studied, and numerous transcription factors are known to function as master regulators of xenobiotic metabolism, disposition, toxicity, and drug-drug interactions. For example, nuclear hormone receptors pregnane X receptor, liver X receptor, or constitutive androstane receptor are known to regulate cytochrome P450s, phase II metabolism enzymes, and transporters including Pgp or members of the multidrug resistance protein (MRP) family (Chan et al., 2004), but surprisingly, not BCRP (Assem et al., 2004; Klucken et al., 2000). Regulation of BCRP is not completely understood but was found to be affected by other pathways such as hypoxia-inducible factor (Krishnamurthy et al., 2004) and sex hormones (Ee et al., 2004). Only recently did Ebert et al. (2005) identify that activation of AhR could induce the expression of BCRP. Interestingly, AhR appears to regulate the induction of the CYP1 family, BCRP, and MRPs but does not induce Pgp (Colombo et al., 2003). Thus, it appears that, although BCRP is localized on the apical surface of polarized cells like Pgp and shares a wide range of substrate specificity with Pgp, the regulation of BCRP and Pgp is distinguished by the activation of different transcription factors. This distinction may provide a compensatory mechanism in the cellular defense system, such that, when one pathway is blocked, the other can compensate. It is well established that food components like flavonoids can induce gene expression through transcription factors including AhR (Hankinson, 1995). With the recent finding that AhR regulates BCRP expression, the authors wisely speculated and carried out additional experiments to evaluate the induction of BCRP by a wide range of phytochemicals. Flavonoids such as chrysin, flavone, quercetin and genistein, silymarin, curcumin, and dibenzoylmethane are known AhR agonists. Tert-butyl hydroquinone (TBHQ), which is a synthetic antioxidant, quercetin, diethylmaleate, and isothiocyanate sulforaphane were used to differentiate the AhR-xenobiotic 1 For correspondence via fax: (609) 818-7130. E-mail: mengmeng.wang@ bms.com.