The breast cancer resistance protein (Bcrp1/Abcg2) restricts exposure to the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.

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.

[1]  L. Doyle,et al.  A multidrug resistance transporter from human MCF-7 breast cancer cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[2]  T. Sugimura,et al.  Presence of carcinogenic heterocyclic amines in urine of healthy volunteers eating normal diet, but not of inpatients receiving parenteral alimentation. , 1991, Carcinogenesis.

[3]  M Kulldorff,et al.  2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, a carcinogen in high-temperature-cooked meat, and breast cancer risk. , 2000, Journal of the National Cancer Institute.

[4]  H. Ohgaki,et al.  Induction of Lymphoma in CDF1 Mice by the Food Mutagen, 2‐Amino‐l‐methyl‐6‐phenylimidazo[4,5‐b]pyridine , 1989, Japanese journal of cancer research : Gann.

[5]  T. Litman,et al.  Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. , 1999, Cancer research.

[6]  N Ito,et al.  A new colon and mammary carcinogen in cooked food, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). , 1991, Carcinogenesis.

[7]  K T Bogen,et al.  Cancer risk of heterocyclic amines in cooked foods: an analysis and implications for research. , 1995, Carcinogenesis.

[8]  A. V. Van Gennip,et al.  Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo. , 2001, Carcinogenesis.

[9]  Y. Miki,et al.  C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. , 2002, Molecular cancer therapeutics.

[10]  J. Cerhan,et al.  Well-done meat intake and the risk of breast cancer. , 1998, Journal of the National Cancer Institute.

[11]  Ryohei Hasegawa,et al.  Dose‐dependent Induction of Mammary Carcinomas in Female Sprague‐Dawley Rats with 2‐Amino‐l‐methyl‐6‐phenylimidazo[4,5‐b]pyridine , 1996, Japanese journal of cancer research : Gann.

[12]  N Ito,et al.  Dose-dependence of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) carcinogenicity in rats. , 1993, Carcinogenesis.

[13]  J. Schellens,et al.  Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. , 2000, Journal of the National Cancer Institute.

[14]  M. Kool,et al.  Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA. , 1998, The Journal of clinical investigation.

[15]  J. Schellens,et al.  Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. , 2002, Molecular cancer therapeutics.

[16]  T. Sugimura,et al.  Strain differences of rats in the susceptibility to aberrant crypt foci formation by 2-amino-1-methyl-6-phenylimidazo- [4,5-b]pyridine: no implication of Apc and Pla2g2a genetic polymorphisms in differential susceptibility. , 1999, Carcinogenesis.

[17]  S. Manabe,et al.  Detection of a carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), in cigarette smoke condensate. , 1991, Carcinogenesis.

[18]  H. Rosing,et al.  The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[19]  D. Meijer,et al.  Heterologous expression of various P-glycoproteins in polarized epithelial cells induces directional transport of small (type 1) and bulky (type 2) cationic drugs. , 1998, The Journal of pharmacology and experimental therapeutics.

[20]  I. Schoots,et al.  Increased bioavailability of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in MRP2-deficient rats. , 2001, Molecular pharmacology.

[21]  F. Hatch,et al.  The isolation and identification of a new mutagen from fried ground beef: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). , 1986, Carcinogenesis.

[22]  J. Schuetz,et al.  Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Schellens,et al.  Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  L B Fay,et al.  Heterocyclic aromatic amine formation in grilled bacon, beef and fish and in grill scrapings. , 1993, Carcinogenesis.

[25]  A. Pardee.  Role Reversal for Anticancer Agents , 2002, Cancer biology & therapy.

[26]  P. Borst,et al.  Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. , 1995, The Journal of clinical investigation.

[27]  T. Litman,et al.  Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. , 1999, Cancer letters.

[28]  M. Barrand,et al.  Localisation of breast cancer resistance protein in microvessel endothelium of human brain , 2002, Neuroreport.

[29]  E. Schuetz,et al.  Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine. , 2003, Pharmacogenetics.

[30]  T. Shirai,et al.  Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) in the rat prostate and induction of invasive carcinomas by subsequent treatment with testosterone propionate. , 1999, Cancer letters.