The diarrhetic shellfish toxin, okadaic acid, administered to rats by intragastric intubation, caused intestinal damage, diarrhea and death, but had no detectable effect on the liver. In contrast, okadaic acid administered intravenously had little effect on intestinal function, but caused a rapid dissolution of hepatic bile canalicular actin sheaths, congestion of blood in the liver, hypotension and death at high doses. In isolated rat hepatocytes, okadaic acid induced disruption of the canalicular sheaths as well as of the keratin intermediate filament network. Both of these cytoskeletal changes could be prevented by addition of a cytoprotective flavonoid, naringin, to the isolated hepatocytes, whereas intravenously or intragastrically administered naringin failed to protect against the effects of okadaic acid in vivo. Freshly isolated colonocytes already had fragmented keratin and tubulin cytoskeletons, died rapidly and were not further afflicted by okadaic acid. Naringin had no protective effect on isolated colonocytes or on intestinal function in vivo, but the nonspecific protein kinase inhibitor, K-252a, and the protein-tyrosine-phosphatase inhibitor, vanadate, significantly reduced the extent of colonocytic keratin fragmentation, and an inhibitor of apoptotic caspases, zVAD.fmk, was strongly protective. Further studies of hepatic and intestinal cytoprotectants should focus on conditions that limit their effectiveness in vivo.