| [ Summary ] |
Cholera toxin (CT) is a major virulence factor produced by Vibrio cholerae, a causative agent of cholera. The severe watery diarrhea observed in patients with cholera is mediated by cholera toxin-catalyzed ADP-ribosylation. The enzymatic A subunit of cholera toxin ADP-ribosylates a GTP-binding protein (Gs alpha) on host cell membranes, leading to cellular malfunction, which results in abnormalities in fluid and electrolyte flux in the small intestine. A commonly used therapy for cholera is administration of an oral rehydration solution (ORS). Although ORS effectively facilitates recovery of cholera patients from dehydration, the combination of ORS with other pharmacological agents that suppress the severe diarrhea would be enormously advantageous. Because Kampo formulations have traditionally been used as a remedy for diarrhea and other gastrointestinal diseases in China and Japan, we decided to examine the inhibitory effects of Kampo formulations on CT-induced elongation of Chinese Hamster Ovary (CHO) cells and ADP-ribosylation. The Kampo formulations, especially Daio-kanzo-to and its Daio component, exerted inhibitoly effects on CT-induced elongation of CHO cells and CTA-catalyzed ADP-ribosylation of Gs alpha. The CT-induced fluid accumulation in mouse intestinal loops was also dose-dependently inhibited by Daio. These results suggest the possibility that Daio can be used to control the severe diarrhea seen in cholera patients, when given in conjunction with ORS therapy.
We are now planning to characterize the inhibitory elements in Daio and consequently to assess the use of Kampo formulations clinically. |