title: Acyclovir is a substrate for the human breast cancer resistance protein (BCRP/ABCG2): implications for renal tubular transport and acyclovir-induced nephrotoxicity.
abstract: The human breast cancer resistance protein (BCRP/ABCG2) is widely expressed in human tissues, including the kidney. In mice, Bcrp1 (murine BCRP ortholog) mediates the transport of acyclovir into breast milk. It is plausible that acyclovir is also a substrate for the human BCRP. The objective of the study was to determine whether acyclovir is a substrate for human BCRP. Transfected human embryonic kidney (HEK293) cells (containing the wild-type ABCG2 gene) were exposed to [8-(14)C]acyclovir (1 µmol/L) in the presence or absence of the BCRP inhibitor fumitremorgin C (FTC). Intracellular acyclovir accumulation was assessed using a liquid scintillation counter. Coexposure to FTC resulted in a significant (5-fold) increase in the intracellular accumulation of acyclovir. The results suggest that acyclovir is a substrate for human BCRP. The study is the first to provide direct evidence for the role of human BCRP in acyclovir transport and its potential significance with respect to renal tubular transport of acyclovir and the direct renal tubular insult induced by the drug.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Patrina
authors.initials: P
authors.lastname: Gunness
authors.forename: Katarina
authors.initials: K
authors.lastname: Aleksa
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism; D000212:Acyclovir / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity*; D001692:Biological Transport / Q000187:drug effects; D002461:Cell Line, Transformed; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D000212:Acyclovir