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)Long Evans Cinnamon(Long Evans Cinnamon，Long Evans Cinnamon)大鼠表现为自发性遗传性肝炎和肝癌，Long Evans Cinnamon(Long Evans Cinnamon，LEC)大鼠具有抗肝微粒体蛋白的自身免疫抗体，尤其是相对分子质量为56kD和55kD的蛋白。NH2末端氨基酸序列分析表明，这两种抗原蛋白分别为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抗原蛋白。(2)用免疫印迹和放射免疫分析方法研究了不同肝毒药物对PDI自身解毒作用的影响。D-氨基半乳糖、扑热息痛+马来酸二乙酯、四氯化碳+马来酸二乙酯预处理的大鼠可检测到较高频率的抗PDI自身抗体。在给予四氯化碳、对乙酰氨基酚、…的大鼠中，抗体阳性率相对较低更多的伊诺芬或单独的DL-乙硫氨酸。单独用顺丁烯二酸二乙酯处理的大鼠未检测到抗PDI抗体。虽然抗PDI自身抗体的产生机制尚不清楚，但抗PDI抗体的产生与血清GPT活性的升高有关。(3)给LEC大鼠口服免疫抑制剂环孢素A和促进铜排泄的D-青霉胺23周。测定死亡率、血液生化指标和血清抗PDI抗体效价。在对照组LEC大鼠中，8只大鼠中有4只在20周前死亡。环孢素A治疗组的7只大鼠中只有1只在20周龄时死亡。用D-青霉胺治疗后，大鼠肝炎的临床症状发展受到抑制，所有大鼠均存活。环孢素-A处理组大鼠的血液生化指标与对照组相似。死亡大鼠的抗PDI抗体滴度明显高于存活大鼠。这些发现表明，抗PDI抗体与LEC大鼠的致死率有关，但与LEC大鼠血液生化参数所测量的肝炎的明显发展和进展无关。较少

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[