title: The role of the efflux carriers Abcg2 and Abcc2 for the hepatobiliary elimination of benzo[a]pyrene and its metabolites in mice.
abstract: The ATP-binding cassette transporters Breast Cancer Resistance Protein (Abcg2) and Multidrug Resistance-associated Protein 2 (Abcc2) play an important role for the hepatobiliary elimination of drugs and toxins as well as their metabolites. Previous in vitro transport studies showed that both transporters are involved in the active efflux of phase II metabolites of carcinogenic benzo[a]pyrene (BP), however the role of these carriers in hepatobiliary elimination in vivo is still unknown. In the present study, Abcg2(-/-) and Abcc2(-/-) knockout mice were used to elucidate the role of Abcg2 and Abcc2 for the hepatobiliary excretion of BP and its metabolites. After intravenous application of [(3)H]BP the hepatobiliary excretion was significantly reduced in these mice: whereas wild type mice excreted on average 25.4% of the applied dose into the bile over 90min, Abcg2(-/-) knockout mice only excreted 10.7% and Abcc2(-/-) knockout mice 8.6%. As a consequence, [(3)H]BP concentrations were in general higher in the plasma and in most of the organs of the Abcg2 and Abcc2 knockout mice. Both transporters may have a protective function for BP-induced carcinogenesis in humans, due to its crucial importance for the hepatobiliary elimination of BP via bile. Subjects with reduced ABCG2 or ABCC2 expression might have higher oral bioavailability for BP due to a reduced excretion and so might be more susceptible to BP-induced carcinogenesis.
authors.affiliation: Institute of Pharmacology and Toxicology, Justus Liebig University of Giessen, Schubert Str. 81, 35392 Giessen, Germany. Electronic address: Jasmin.Kranz@vetmed.uni-giessen.de.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Kranz
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. Electronic address: stefanie.hessel@bfr.bund.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hessel
authors.affiliation: Institute of Pharmacology and Toxicology, Justus Liebig University of Giessen, Schubert Str. 81, 35392 Giessen, Germany. Electronic address: Julia.Aretz@vetmed.uni-giessen.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Aretz
authors.affiliation: Biochemical Institute for Environmental Carcinogens (BIU), Prof. Dr. Gernot Grimmer Foundation, Lurup 4, 22927 Grosshansdorf, Germany. Electronic address: albrecht.seidel@biu-grimmer.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Seidel
authors.affiliation: Institute of Pharmacology and Toxicology, Justus Liebig University of Giessen, Schubert Str. 81, 35392 Giessen, Germany. Electronic address: Ernst.Petzinger@vetmed.uni-giessen.de.
authors.forename: Ernst
authors.initials: E
authors.lastname: Petzinger
authors.affiliation: Institute of Pharmacology and Toxicology, Justus Liebig University of Giessen, Schubert Str. 81, 35392 Giessen, Germany. Electronic address: Joachim.M.Geyer@vetmed.uni-giessen.de.
authors.forename: Joachim
authors.initials: J
authors.lastname: Geyer
authors.affiliation: Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str. 8-10, 10589 Berlin, Germany. Electronic address: alfonso.lampen@bfr.bund.de.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lampen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D000818:Animals; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000378:metabolism*; D001646:Bile / Q000378:metabolism*; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D001564:Benzo(a)pyrene; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; C000715087:ABCC2 protein, human; C501412:Abcg2 protein, mouse
keywords: Abcc2; Abcg2; Benzo[a]pyrene; Hepatobiliary excretion