title: Critical roles of Rho-associated kinase in membrane blebbing and mitochondrial pathway of apoptosis caused by 1-butanol.
abstract: Alcohols are widely used as industrial solvents and chemical intermediates but can cause serious damage to human health. Nevertheless, few studies have addressed the molecular mechanisms underlying the cytotoxicity of industrial alcohols, with the notable exception of ethanol. The goal of our current study is to elucidate the molecular mechanism of cytotoxicity caused by primary alcohols containing longer carbon chains than ethanol. We find that 1-butanol induces morphological changes in H9c2 cardiomyoblastoma including nuclear condensation and membrane blebbing, both of which are features of apoptotic response. Moreover, a decrease in the mitochondrial membrane potential, the cytosolic release of cytochrome c, and the activation of caspase 9 and 3 was observed, thus revealing the activation of the mitochondrial apoptotic pathway by 1-butanol. The addition of Y-27632, a specific inhibitor of Rho-associated kinase (ROCK), suppressed the membrane blebbing and mitochondrial apoptotic pathway. In comparison z-VAD-fmk, a pan-caspase inhibitor, did not inhibit membrane blebbing but did prevent cell death following exposure to 1-butanol. These results indicate that mitochondrial pathway of apoptosis and membrane blebbing are parallel phenomena that occur downstream of ROCK. This kinase thus plays an essential role in 1-butanol cytotoxicity and subsequent cell death in H9c2 cells.
authors.affiliation: Section of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Noritake
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Aki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Funakoshi
authors.forename: Kana
authors.initials: K
authors.lastname: Unuma
authors.forename: Akina
authors.initials: A
authors.lastname: Nara
authors.forename: Chizuru
authors.initials: C
authors.lastname: Kato
authors.forename: Koichi
authors.initials: K
authors.lastname: Uemura
mesh_terms: D020001:1-Butanol / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012997:Solvents / Q000633:toxicity*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D012997:Solvents; D020001:1-Butanol; D054460:rho-Associated Kinases