title: Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes.
abstract: Bucillamine is used for the treatment of rheumatoid arthritis. This study investigated the protective effects of bucillamine against cisplatin-induced damage in auditory cells, the organ of Corti from postnatal rats (P2) and adult Balb/C mice. Cisplatin increases the catalytic activity of caspase-3 and caspase-8 proteases and the production of free radicals, which were significantly suppressed by pretreatment with bucillamine. Bucillamine induces the intranuclear translocation of Nrf2 and thereby increases the expression of γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GSS), which further induces intracellular antioxidant glutathione (GSH), heme oxygenase 1 (HO-1) and superoxide dismutase 2 (SOD2). However, knockdown studies of HO-1 and SOD2 suggest that the protective effect of bucillamine against cisplatin is independent of the enzymatic activity of HO-1 and SOD. Furthermore, pretreatment with bucillamine protects sensory hair cells on organ of Corti explants from cisplatin-induced cytotoxicity concomitantly with inhibition of caspase-3 activation. The auditory-brainstem-evoked response of cisplatin-injected mice shows marked increases in hearing threshold shifts, which was markedly suppressed by pretreatment with bucillamine in vivo. Taken together, bucillamine protects sensory hair cells from cisplatin through a scavenging effect on itself, as well as the induction of intracellular GSH.
authors.affiliation: Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea.
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Emergency medicine, Wonkwang University, College of Medicine, Iksan, Jeonbuk, Korea.
authors.forename: Joon
authors.initials: J
authors.lastname: Ho Hur
authors.affiliation: Department of Head & Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Channy
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea.
authors.forename: Hyung-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea.
authors.forename: Gi-Su
authors.initials: GS
authors.lastname: Oh
authors.affiliation: Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea.
authors.forename: Joon No
authors.initials: JN
authors.lastname: Lee
authors.affiliation: Emergency medicine, Wonkwang University, College of Medicine, Iksan, Jeonbuk, Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Yoo
authors.affiliation: Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea.
authors.forename: Seong-Kyu
authors.initials: SK
authors.lastname: Choe
authors.affiliation: 1] Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea [2] BK21Plus Program & Department of Smart Life-Care Convergence, Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea.
authors.forename: Hong-Seob
authors.identifier: 0000000151108351
authors.initials: HS
authors.lastname: So
authors.affiliation: Department of Head & Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lim
authors.affiliation: Department of Head & Neck Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Sung K
authors.initials: SK
authors.lastname: Moon
authors.affiliation: 1] Department of Microbiology, Center for Metabolic Function Regulation (CMFR), Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea [2] BK21Plus Program & Department of Smart Life-Care Convergence, Wonkwang University College of Medicine, Iksan, Jeonbuk, Korea.
authors.forename: Raekil
authors.initials: R
authors.lastname: Park
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000633:toxicity*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D050217:Metabolic Detoxication, Phase II / Q000235:genetics; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis; D009925:Organ of Corti / Q000187:drug effects* / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D053148:Caspase 3; D053181:Caspase 8; D002945:Cisplatin; D003545:Cysteine; D005978:Glutathione; D051547:Heme Oxygenase-1; D051267:NF-E2-Related Factor 2; D009569:Nitric Oxide; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C026535:bucillamine