title: The role of breast cancer resistance protein (BCRP/ABCG2) in cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors.
abstract: Treatment of HIV-1-infected patients with anti-retroviral agents is not always successful due to the emergence of resistant HIV-1 mutants with reduced susceptibility to the agents. However, factors other than viral mutation may also contribute to treatment failure. It has been demonstrated that the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp/ABCB1) is a key determinant of oral bioavailability of HIV-1 protease inhibitors and their penetration of the central nervous system. More recently, we have found that the expression of breast cancer resistance protein (BCRP/ABCG2) in a CD4+ T-cell line confers cellular resistance to nucleoside reverse transcriptase inhibitors (NRTIs). The anti-HIV-1 activity of the NRTI zidovudine (AZT) was significantly diminished through the reduction of its metabolite levels in MT-4 cells which express high levels of BCRP. Moreover, the BCRP-specific inhibitor fumitremorgin C could completely restore the cytotoxicity of AZT and intracellular levels of its metabolites in BCRP-expressing cells. Thus, BCRP is considered to be a cellular factor that modulates the anti-HIV-1 activity of NRTIs.
authors.affiliation: Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical & Dental Sciences, Kagoshima University, Kagoshima, Japan. xinwang@m2.kufm.kagoshima-u.ac.jp
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D019380:Anti-HIV Agents / Q000494:pharmacology; D001693:Biological Transport, Active; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002460:Cell Line; D024921:Drug Resistance, Multiple, Viral; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000502:physiology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013997:Time Factors
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D019380:Anti-HIV Agents; D007211:Indoles; D009363:Neoplasm Proteins; D018894:Reverse Transcriptase Inhibitors; C010522:tryptoquivaline