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© 1998 Oxford University Press
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Prolonged Sublethal Exposure to the Protein Phosphatase Inhibitor Microcystin-LR Results in Multiple Dose-Dependent Hepatotoxic Effects
*College of Veterinary Medicine. University of Illinois 2001 South Lincoln Avenue, Urbana. Illinois 61802
Food Research Institute and Department of Food Microbiology and Toxicology, University of Wisconsin—Madison 1925 Willow Drive. Madison, Wisconsin 53706-1187
Division of Gastrointestinal and Liver Diseases, Department of Medicine. University of Southern California School of Medicine Los Angeles, Califomia 90033
Received September 11, 1997; accepted April 14, 1998
The purpose of this study was to relate dose-dependent hepatotoxicity stemming from prolonged exposure to sublethal concentrations of the cyclic heptapeptide microcystin-LR (Mcyst) to hepatic Mcyst concentrations and protein phosphatase activity. Mcyst is a potent inhibitor of protein phosphatase types 1 and 2A (PP1 and PP2A). Twenty male Sprague-Dawley rats were infused continuously with 0, 3, 6, or 9 µg Mcyst/days for 28 days using intraperitoneal mini-osmotic pumps containing highly purified toxin or saline. At the end of 28 days, dose-dependent increases in several serum biochemical tests including sorbitol dehydrogenase, aspartate amhotransferase, 
-glutamyl transferase, alkaline phosphatase, and bile acids had occurred. Serum albumin decreased in a dose-dependent fashion. Liver activity of both PP1 and PP2A decreased in a dose-dependent manner, but with a relatively greater effect on PP2A than PP1. Liver cytosol Mcyst concentrations, measured by direct competitive ELISA, also increased in a dose-dependent manner, although at a higher rate than would be predicted from the incremental increase in dose given. This disproportional increase is suggestive of the bioaccumulation of Mcyst with increasing dose. Histopathological abnormalities included hepatocellular apoptosis and cytosolic vacuolation of principally zone 3 hepatocytes. Immunohistochemical stains revealed Mcyst predominantly within pericanalicular regions of zone 3 hepatocytes. It was concluded that prolonged exposure to sublethal concentrations of Mcyst results in multiple dose-depen-dent hepatotoxic effects that correspond to decreased hepatic serine/threonine protein phosphatase activity and increasing cytosolic Mcyst concentrations. The disproportional increase of hepatic Mcyst concentrations observed may suggest the bioaccumulation of toxin and an increasing relative risk of hepatotoxicity with increasing dose.
Key Words: apoptosis; histopathology; immunohistochemistry; liver; microcystin-LR; protein phosphatase; rats; serum biochemistry; toxin.
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