Bucillamine prevents cisplatin-induced ototoxicity through induction of glutathione and antioxidant genes.
- Author:
Se Jin KIM
1
;
Joon Ho HUR
;
Channy PARK
;
Hyung Jin KIM
;
Gi Su OH
;
Joon No LEE
;
Su Jin YOO
;
Seong Kyu CHOE
;
Hong Seob SO
;
David J LIM
;
Sung K MOON
;
Raekil PARK
Author Information
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- MeSH: Animals; Antioxidants/*metabolism/*pharmacology; Apoptosis/drug effects; Caspase 3/metabolism; Caspase 8/metabolism; Cell Line; Cisplatin/*toxicity; Cysteine/*analogs & derivatives/pharmacology; Gene Expression Regulation/*drug effects; Gene Knockdown Techniques; Glutathione/*metabolism; Heme Oxygenase-1/genetics; Intracellular Space/metabolism; Male; Metabolic Detoxication, Phase II/genetics; Mice; NF-E2-Related Factor 2/genetics; Nitric Oxide/biosynthesis; Organ of Corti/*drug effects/*metabolism; RNA Interference; Rats; Reactive Oxygen Species/metabolism; Superoxide Dismutase/genetics
- From:Experimental & Molecular Medicine 2015;47(2):e142-
- CountryRepublic of Korea
- Language:English
- 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 gamma-glutamylcysteine synthetase (gamma-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.
