The important role of BCRP for in vivo disposition of benzo[a]pyrene conjugates in the liver and intestine

Purpose: In vitro transport studies in the human intestinal Caco-2 cells revealed that the ATP-binding cassette carrier Breast Cancer Resistance Protein (BCRP) is involved in the active efflux of phase II metabolites of benzo[a]pyrene (BP). Therefore we investigated the metabolism and excretion of BP in vivo using the bcrp-/- knockout mice. Besides BCRP, several xenobiotic metabolizing enzymes are involved in the detoxification of BP, and these can be induced by the aryl hydrocarbon receptor (AhR). The flavonoid quercetin have been identified as AhR agonists suggesting that these compounds can promote detoxification and elimination of dietary toxins such as BP. Methods: Bcrp-/- knockout mice and bcrp+/+ wild-type FVB mice were exposed i.v. and p.o. to BP (1.0mg/kg), including 3µCi of the radiolabeled BP per mouse. Additionally, mice were fed for 3 days with 10 mg/kg quercetin before administration of BP. Blood and bile samples were collected and at the last indicated time point; the organs were removed and homogenized. The levels of radioactivity were quantified by a Wallac 1409 liquid scintillation counter. Results: In BCRP-deficient mice, hepatobiliary excretion of BP metabolites significantly decreased compared to wild-type mice and also intestinal secretion of BP was significantly reduced. Additionally, bcrp-/- knockout mice showed higher plasma and liver levels of BP compared to wild-type mice clearly show the important role of BCRP in BP elimination also in vivo. Additionally, quercetin dramatically enhanced the hepatobiliary, urinary and intestinal excretion of BP and reduced the general tissue concentrations compared with non-quercetin fed mice.