The function of breast cancer resistance protein in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins

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The breast cancer resistance protein [BCRP (also known as ABCG2)] belongs to the ATP binding cassette (ABC) family of transmembrane drug transporters. BCRP has a broad substrate specificity and actively extrudes a wide variety of drugs, carcinogens and dietary toxins from cells. Situated in the apical plasma membrane of epithelial cells of the small and large intestine and renal proximal tubules and in the bile canalicular membrane of hepatocytes, BCRP decreases the oral availability and systemic exposure of its substrates. In several blood–tissue barriers BCRP reduces tissue penetration of its substrates and it protects haematopoietic stem cells from cytotoxic substrates. Moreover, BCRP is expressed in mammary gland alveolar epithelial cells during pregnancy and lactation, where it actively secretes a variety of drugs, toxins and carcinogens into milk. In apparent contradiction with the detoxifying role of BCRP in mothers, this contamination of milk exposes suckling infants and dairy consumers to xenotoxins. BCRP thus affects many important aspects of pharmacology and toxicology.

Section snippets

BCRP, a pharmacologically important ABC multidrug transporter

Multidrug transporters of the ATP binding cassette (ABC) family are membrane-spanning efflux pumps that can actively extrude a wide range of structurally different drugs, carcinogens and other xenotoxins across the plasma membrane of cells. This ATP-dependent efflux can occur against steep concentration gradients. In this way, ABC transporters can confer multidrug resistance to tumour cells. Moreover, several of these transporters have prominent physiological roles in the body because they

Biochemical properties and substrate specificity of BCRP

BCRP was named breast cancer resistance protein merely because it was first cloned from a multidrug-resistant breast cancer cell line. However, there is no indication that BCRP is specific or even typical for breast cancer cells because many of these cells lack substantial BCRP expression. By its localization in the plasma membrane BCRP can actively extrude a wide variety of drugs, such as the anticancer drugs mitoxantrone, topotecan and methotrexate, from cells, thus conferring resistance to

BCRP limits the oral availability of drugs and mediates their excretion

Both in humans and in mice, BCRP/BCRP1 is situated strategically in the apical membrane of epithelial cells of the small and large intestine and in the bile canalicular membrane of hepatocytes (Figure 2). This enables BCRP/BCRP1 to limit the oral availability of its substrates by mediating rapid hepatobiliary and direct intestinal excretion, and probably also by reducing net uptake from the gut lumen. This is supported by several studies. For example, because of the lack of BCRP1, the plasma

BCRP/BCRP1 protects crucial tissues from xenotoxins

BCRP and BCRP1 are abundant in the luminal membrane of endothelial cells of blood capillaries in the brain and in placental syncytiotrophoblasts, where they can limit the penetration of xenotoxins across the blood–brain and maternal–foetal barriers, respectively (Figure 2). The foetal penetration of topotecan, for example, is twofold increased in mice when placental BCRP1 is absent [7]. In the brain of BCRP1-deficient mice, compared with wild-type mice, a twofold higher penetration of the

BCRP/BCRP1 protects organisms from natural dietary toxins

A striking illustration of the role of BCRP1 in protection from natural xenotoxins has been observed in BCRP1-deficient mice. These mice displayed a highly increased susceptibility to phototoxicity compared with wild-type mice, resulting in severe ear lesions [7]. This phenotype was caused by the dietary phototoxin ‘pheophorbide a’, a chlorophyll-breakdown product that can be found in several animal feeds and sometimes in human food supplements. Whereas wild-type mice are protected efficiently

BCRP/BCRP1 expression in stem cells and progenitor cells

In stem cell research, the capacity to efflux the fluorescent dye Hoechst 33342 is an important marker for the isolation of haematopoietic stem cells from bone marrow (Figure 3) [14]. This efflux capacity of Hoechst 33342 by stem cells, resulting in a side population (SP) in fluorescence-activated cell sorting (FACS) plots with a characteristic amount and ratio of ‘blue’ versus ‘red’ fluorescence, is conferred by BCRP1 [15]. BCRP1 is expressed at substantial levels in primitive murine

Implications for BCRP inhibitor use in cancer chemotherapy

The protective role of BCRP/BCRP1 in haematopoietic and possibly other tissue stem cells might complicate the application of efficacious BCRP inhibitors to improve the chemotherapy response of BCRP-expressing tumours. The expression of BCRP in human leukaemias and solid tumours has been demonstrated in several studies, some of which can associate BCRP expression with relapse or refractory disease, or as a prognostic factor for overall survival 5, 25. To specifically enhance the availability of

Drug and xenotoxin secretion into milk

Many unique advantages of human breast milk for providing infant nutrition support the major trend in the developed world to return to breast-feeding. However, concerns have been raised over maternal drug transfer to the suckling infant [26]. Although breast-feeding women can take several drugs safely, reports of toxicity in breast-fed infants as a result of pharmacologically significant levels of drug exposure exist [27]. Importantly, environmental and dietary toxins and carcinogens, in

BCRP secretes drugs and xenotoxins into milk

BCRP/BCRP1 was identified recently as a major factor in the active secretion of xenotoxins into milk [33]. Whereas BCRP1 is not expressed in mammary epithelial tissue of virgin mice, it is strongly induced during late pregnancy and particularly during lactation. BCRP1 is located primarily in the apical membrane of alveolar epithelial cells (i.e. at the main site of milk production) but not in main ducts (Figure 2) [33]. To assess the functional role of BCRP1 in the mammary gland, the milk

BCRP1-mediated secretion of carcinogens into milk

In addition to PhIP, two other heterocyclic amine dietary carcinogens, IQ and Trp-P-1, are secreted into milk by BCRP1, albeit not as efficiently as PhIP. The same applies to the potent human hepatocarcinogen aflatoxin B1 (Table 1) [24]. Aflatoxin B1 is one of the most potent mycotoxins known to man and an important risk factor for the development of hepatocellular carcinoma in humans 36, 37. This BCRP1-mediated active transfer of xenotoxins can be a serious health threat: for example, milk

Pharmacological implications of BCRP expression in the mammary gland

The expression of BCRP in the mammary gland during lactation is conserved in cows and humans [33]. Given the similarity in substrates transported by mouse and human BCRP [4], the clinical significance of BCRP activity in the lactating mammary gland is evident: drugs and drug metabolites that are good BCRP substrates have a high chance of being concentrated into milk and should thus be examined carefully for the risk of dangerously increased exposure levels in infants or dairy consumers. The

Endogenous role of BCRP1 expression in the mammary gland?

The physiological function of BCRP in secreting xenotoxins into milk is puzzling because this activity potentially exposes the vulnerable suckling infant to a range of xenotoxins. Everywhere else in the body BCRP appears to have a xenotoxin-protective role, including protection of the foetus before birth. One option is that BCRP might be used to secrete a variety of nutrients into milk, offsetting the risk of xenotoxin contamination. However, several obvious candidate nutrients that are known

Concluding remarks

The aforementioned studies have revealed several new and important pharmacological and toxicological functions of BCRP. The activity of BCRP in haematopoietic and other stem and progenitor cells might affect the sensitivity of patients to dose-limiting side-effects of cancer chemotherapy and the chemotherapy response of tumours. BCRP activity can vary extensively because of: (i) known genetic polymorphisms and gender 44, 45, 46, 47; (ii) intentional or coincidental use of drugs that inhibit

Acknowledgements

We thank J.W. Jonker and the audiovisual centre NKI for kindly providing Figure 1, Figure 2, respectively. We thank M. Vlaming, E. van de Steeg and J.H. Beijnen for useful comments on the text. This work was supported in part by grants from the Dutch Cancer Society and NWO/STW.

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