Cepharanthine, an anti-inflammatory drug, suppresses mitochondrial membrane permeability transition.
Cepharanthine (CEP), a biscocrourine alkaloid, has been widely used in Japan for the treatment of several disorders. Furthermore, accumulated evidence shows that CEP protects against some cell death systems but not others. Recently, it was found that mitochondria play an important role in a mechanism of apoptosis involving membrane permeability transition (MPT). Although CEP stabilizes the mitochondrial membrane structure and protects some functions of mitochondria from damage, the mechanism of action of CEP on MPT remains obscure. In this study, therefore, we examined the effect of CEP on Ca2+- and Fe2+/ADP-induced MPT of isolated mitochondria. CEP inhibited Ca2+-induced swelling, depolarization, Cyt.c release, and the release of Ca2+ in a concentration dependent manner. CEP also inhibited Ca2+-induced generation of reactive oxygen species and Fe/ADP-induced swelling and lipid peroxidation. Furthermore, CEP suppressed Ca2+-induced thiol modification of adenine nucleotide transloase (ANT). These results suggested that CEP suppressed MPT by a decrease in affinity of cyclophilin D for ANT. From these results it was concluded that the suppression of MPT by CEP might be due to its inhibitory action on Ca2+ release and antioxidant activity and that CEP might suppress the mechanism of apoptotic cell death when directly interacted with mitochondria in cells.
Nagano
Makoto
M
Institute of Medical Science, Kurashiki Medical Center Kurashiki 710-8522, Japan.
Kanno
Tomoko
T
Fujita
Hirofumi
H
Muranaka
Shikibu
S
Fujiwara
Takuzo
T
Utsumi
Kozo
K
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D044182:Benzylisoquinolines; D002118:Calcium / Q000378:metabolism*; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007425:Intracellular Membranes / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D052117:Benzodioxoles
D000470:Alkaloids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D044182:Benzylisoquinolines; D002118:Calcium; D017382:Reactive Oxygen Species; C006947:cepharanthine; D052117:Benzodioxoles