Abstract
The food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine found in various protein containing foods. PhIP is mutagenic and carcinogenic in rodents, inducing lymphomas in mice and colon, mammary and prostate carcinomas in rats. It has also been implicated in human breast carcinogenesis. Humans on a normal Western diet are exposed to PhIP on a daily basis. The breast cancer resistance protein (BCRP/ABCG2) transports various anticancer drugs from cells, causing multidrug resistance. By its presence in the apical membrane of the intestine and bile canalicular membrane, it also protects the body from substrate drugs and toxins. We investigated whether Bcrp1 could affect PhIP exposure of the body because this could implicate BCRP activity in the cancer risk due to PhIP. Using polarized cell lines, we found that PhIP is efficiently transported by murine Bcrp1. In vivo pharmacokinetic studies showed that at a dose of 1 mg/kg [(14)C]PhIP the area under the curve for oral administration was 2.9-fold higher in Bcrp1(-/-) compared with wild-type mice (306 +/- 39 versus 107 +/- 15 h.ng/ml) and, for i.v. administration, 2.2 fold higher (386 +/- 36 versus 178 +/- 8.9 h.ng/ml). Wild-type mice cleared [(14)C]PhIP mainly by fecal excretion, but this shifted to primarily urinary excretion in Bcrp1(-/-) mice. In mice with a cannulated gall bladder, both hepatobiliary and direct intestinal excretion of [(14)C]PhIP were greatly impaired in Bcrp1(-/-) compared with wild-type mice (9.0 +/- 4.4 versus 36.5 +/- 9.4% and 1.5 +/- 0.8 versus 4.2 +/- 1.5%, respectively). We conclude that Bcrp1 effectively restricts the exposure of mice to ingested PhIP by decreasing its uptake from the gut lumen and by mediating hepatobiliary and intestinal elimination. Intra- or interindividual differences in BCRP activity in humans may thus also affect the exposure to PhIP and related food carcinogens, with possible implications for cancer susceptibility.