SAKUMA Tsutomu Hokkaido Univ., Fac. Pharm. Sci., Assistant Professor, 薬学部, 助手 (30250468)
KAMATAKI Tetsuya Hokkaido Univ., Fac. Pharm. Sci., Professor, 薬学部, 教授 (00009177)
澤田 稔 北海道大学, 薬学部, 助手 (30215917)
伊東 進 北海道大学, 薬学部, 助手 (70223154)
|Budget Amount *help
¥1,900,000 (Direct Cost : ¥1,900,000)
Fiscal Year 1994 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1993 : ¥1,300,000 (Direct Cost : ¥1,300,000)
(1) Long Evans Cinnamon (LEC) rats, showing spontaneous hereditary hepatitis and hepatic carcinoma, were found to possess autoimmune antibodies to liver microsomal proteins, particularly to proteis with the molecular weight of 56kD and 55kD.The antibodies occurred in association with acute lethal hepatitis in the LEC rats. These two antigenic protein were revealed to be protein disulfide isomerase (PDI) and calreticulin, respectively, from NH2-terminal amino acid sequence analysis. PDI was a major autoimmune antigenic protein.
(2) The occurrence of an autoantidody to PDI in rats after administration of various hepatotoxic drugs was investigated by immunoblotting and radiommunoassay. The anti-PDI autoantibody was detected with high frequency in rats pretreated pretreated with D-galactosamine, acetaminophen with diethylmaleate, and carbon tetrachloride with diethylmaleate. The antibody-positive rate was relatively low in the groups of rats given carbon tetrachloride, acetaminophen, acetam
inophen or DL-ethionine alone. The anti-PDI antibody was not detected in rats treated with diethylmaleate alone. Although the mechanism of the production of the anti-PDI autoantibody is unclear, the occurrence of anti-PDI antibody correlated with high serum GPT activities.
(3) Cyclosporin-A,an immunosuppressant, and D-penicillamine, which promotes copper excretion, were orally administered to LEC rats for 23 weeks. Mortality, blood biochemical parameters and the titer of serum anti-PDI antibody were measured. In control LEC rats, four of eight rats died bifore 20-weeks-old. Only one of seven rats in the cyclosporin-A-treated group died at the age of 20 weeks. When rats were treated with D-penicillamine, the development of clinical signs of hepatitis was inhibited, and all rats survived. Cyclosporin-A-treated rats showed increases in blood biochemical parameters similar to those in control rats. The titer of anti-PDI antibody in control rats was higher in the non-survivors than in the survivors. These findings suggest the association of the anti-PDI antibody with lethality, but not with the apparent development and progression of hepatitis as measured by blood biochemical parameters in LEC rats. Less