Can the Occurence of Autoantibody to Protein Disulfide Isomerase be a Marker for the Development of Hepatitis?

蛋白质二硫键异构酶自身抗体的出现可以作为肝炎发展的标志吗？

• 批准号: 05807204
• 负责人: YOKOI Tsuyoshi
• 金额: $ 1.22万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05807204/
• 关键词: Autoimmune antibodies; LEC rats; Hepatitis; Protein disulfide isomerase; Cyclosporin-A; D-Penicillamine; カルレチクリン

(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 … More 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

(1)实验结果表明，具有自发性遗传性肝炎和肝癌表现的Long Evans Cinnamon（LEC）大鼠体内存在抗肝微粒体蛋白的自身免疫抗体，尤其是抗56 kD和55 kD蛋白的抗体，这种抗体与LEC大鼠急性致死性肝炎有关。氨基酸序列分析表明，这两个抗原蛋白分别是蛋白质二硫键异构酶（PDI）和钙网蛋白。PDI是一种主要的自身免疫性抗原蛋白。(2)用免疫印迹和放射免疫分析法研究了不同肝毒性药物给药后大鼠PDI自身抗体的发生。在用D-氨基半乳糖、对乙酰氨基酚和马来酸二乙酯、四氯化碳和马来酸二乙酯预处理的大鼠中检测到高频率的抗PDI自身抗体。四氯化碳组、醋氨酚组、乙酰胺组抗体阳性率较低 ...更多信息 单独使用对羟基苯酚或DL-乙硫醚。在单独给予马来酸二乙酯的大鼠中未检测到抗PDI抗体。尽管抗PDI自身抗体产生的机制尚不清楚，但抗PDI抗体的产生与高血清GPT活性相关。(3)免疫抑制剂环孢素A和促进铜排泄的D-青霉胺口服给LEC大鼠23周。检测各组动物死亡率、血液生化指标及血清抗PDI抗体滴度。对照组8只大鼠中有4只在20周龄前死亡。环孢素A治疗组的7只大鼠中只有1只在20周龄时死亡。当大鼠用D-青霉胺治疗时，肝炎临床体征的发展受到抑制，所有大鼠均存活。环孢素A处理的大鼠显示出与对照大鼠相似的血液生化参数增加。对照组大鼠抗PDI抗体滴度在死亡组高于存活组。这些研究结果表明，抗PDI抗体与致死率的关联，但与LEC大鼠血液生化参数测量的肝炎的明显发展和进展无关。少

项目成果

Kunio Itoh, Teruyuki Kimura, Tsuyoshi Yokoi, Susumu Itoh and Tetsuya Kamataki: "Rat liver flavin-containing monooxygenase (FMO) : cDNA cloning and expression in yeast." Biochim. Biophys. Acta. 1173. 165-171 (1993)

Kunio Itoh、Teruyuki Kimura、Tsuyoshi Yokoi、Susumu Itoh 和 Tetsuya Kamataki：“大鼠肝脏含黄素单加氧酶 (FMO)：cDNA 克隆和在酵母中的表达。”

E.Kashiyama.et al.: "Stereoselective pharmacokinetics and chiral inversions of flosequinan enantiomers containing chiral sulfoxide in rats." Xenobiotica. (in press). (1993)

E.Kashiyama.et al.：“含有手性亚砜的氟喹南对映体在大鼠体内的立体选择性药代动力学和手性反转。”

Yoshiki Takahashi, Susumu Itoh, Tsukasa Shimojima and Tetsuya Kamataki: "Characterization of Ah receptor Promoter in human liver cell line, Hep G2." Pharmacogenetics. 4. 219-222 (1994)

Yoshiki Takahashi、Susumu Itoh、Tsukasa Shimojima 和 Tetsuya Kamataki：“人肝细胞系 Hep G2 中 Ah 受体启动子的表征。”

T.Yokoi et al.: "Identification of protein disulficle isomerose and calreticulin as autoimmune antigens in LEC strain of rats." Biochim.Biophys.Acta. 1158. 339-344 (1193)

T.Yokoi 等人：“鉴定蛋白质二硫异构糖和钙网蛋白作为 LEC 大鼠品系的自身免疫抗原。”

T.Yanagawa et al.: "Stable expression of human CYP1A2 and N-acetyl-transferase:Mutagenic activation of 2-amino-3-methylimidazo[4,5-f]quinoline(IQ)and 2-amino-3,8dimethylimidazo[4,5-f]quinoxaline(MeIQx)." Cancer Res.,. 54. 3422-3427 (1994)

T.Yanakawa 等人：“人 CYP1A2 和 N-乙酰基转移酶的稳定表达：2-氨基-3-甲基咪唑[4,5-f]喹啉 (IQ) 和 2-氨基-3,8 二甲基咪唑的诱变激活[