Biphasic effects of dithiocarbamates on the activity of nuclear factor-kappaB.
Dithiocarbamates are well-known antioxidants and nuclear factor-kappaB (NF-kappaB) inhibitors. Recently, they have been characterized as zinc ionophores. Concentration-dependent biphasic effects of dithiocarbamates on NF-kappaB activity have been widely reported. We studied the mechanism of this phenomenon in relation to Zn(2+) influx. Two dithiocarbamates, pyrrolidine dithiocarbamate and diethyldithiocarbamate, showed concentration-dependent biphasic effects in inhibiting NF-kappaB activation in cerebral endothelial cells. These unique effects of dithiocarbamates on NF-kappaB were tightly linked to their ability to elevate intracellular Zn(2+)500 microM), dithiocarbamates started to lose their ability to promote Zn(2+) influx and to inhibit NF-kappaB activation. These results might provide insight into the appropriate use of dithiocarbamates in various disorders.
Kim
C H
CH
Yonsei Brain Research Institute and Department of Pharmacology, Yonsei University College of Medicine, Seoul, South Korea.
Kim
J H
JH
Moon
S J
SJ
Hsu
C Y
CY
Seo
J T
JT
Ahn
Y S
YS
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply; D004050:Ditiocarb / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000494:pharmacology*; D013859:Thiocarbamates / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism / Q000493:pharmacokinetics
D016328:NF-kappa B; D011759:Pyrrolidines; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D004050:Ditiocarb; D015032:Zinc