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Immunohistochemical Localization of Microcystin-LR in the Liver of Mice: A Study on the Pathogenesis of Microcystin-LR-Induced Hepatotoxicity

Research Institute for Biosciences, Faculty of Pharmaceutical Sciences

Yuki Makita

Department of Toxicology and Microbial Chemistry, Faculty of Pharmaceutical Sciences

Tomoaki Tsutsumi

Research Institute for Biosciences, Faculty of Pharmaceutical Sciences

Satoshi Nagata

Laboratory of Biological Chemistry, Department of Applied Biological Chemistry, Faculty of Agricultural and Life Science, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113–0032, Japan.

Fumio Tashiro

Faculty of Industry and Technology, Science University of Tokyo, Ichigaya, Shinjuku-ku, Tokyo 162–0826, Japan

Fuyuko Yoshida

Research Institute for Biosciences, Faculty of Pharmaceutical Sciences

Masaru Sekuima

Kashima Laboratory, Mitsubishi Chemical Safety Institute, Kashima-gun, Ibaraki 314–0255, Japan

Shin-Ichi Tamura

Departmerit of Pathology, National Institiite o Itfectioris Diseases, Tojania, Shinjirkii-kri, TOX-JO f 162-0052, Japan

Takanori Harada

Toxicology Division, Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303–0043, Japan

Keizo Maita

Toxicology Division, Institute of Environmental Toxicology, Mitsukaido-shi, Ibaraki 303–0043, Japan

Yoshio Ueno

Department of Toxicology and Microbial Chemistry, Faculty of Pharmaceutical Sciences

The relationship between the intralobular sites of hepatotoxic injury and the distribution of microcystin-LR (MCLR), an inhibitor of protein phosphatases 1 (PP1) and 2A (PP2A), was examined using an immunohistochemical method with a monoclonal antibody specific to MCLR on the livers of mice receiving a single ip injection of the MCLR. Immunoblotting and high-performance liquid chromatography analyses of liver extracts were also performed to determine the binding form of MCLR to PP1 and PP2A (MCLR-PP1/PP2A adducts) and free MCLR. Immunohistochemistry revealed a discernible intensity of staining in the centrilobular regions where hemorrhage and apoptosis occurred. In these regions, immunopositivity was evident in the cytoplasm and nuclei of the hepa-tocytes; some apoptotic cells were also immunopositive. In contrast, coaglilative necrosis, which was mainly'evident in the midlobular regions, was completely negative. Analysis of liver extracts demonstrated MCLR-PP1/PP2A adducts, but free MCLR was below detection limit. These results suggest that the immunohistochemical localization of MCLR in centrilobular hepatocytes is closely associated with the onset of hemorrhage and apoptosis and is related to adduct formation. The occurrence of coagulative necrosis however might also be related to other factors such as ischemia/hypoxia.

Key Words: Hepatocyte • hemorrhage • necrosis • apoptosis • protein adducts

Toxicologic Pathology, Vol. 26, No. 3, 411-418 (1998)
DOI: 10.1177/019262339802600316


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