title: Chronological changes in circulating levels of soluble tumor necrosis factor receptors 1 and 2 in rats with carbon tetrachloride-induced liver injury.
abstract: Carbon tetrachloride (CCl₄) facilitates the generation of hepatotoxins that can result in morphologic abnormalities, and these abnormalities are reasonably characteristic and reproducible for each particular toxin. It is also known that tumor necrosis factor-alpha (TNF-α) may participate in CCl₄-induced liver injury (CILI). In this study, we observed the chronological changes in circulating soluble tumor necrosis factor receptors 1 and 2 (sTNF-R1 and -R2) in rats with CILI. Laboratory data; circulating levels of TNF-α, sTNF-R1, and sTNF-R2; and TNF-α levels in liver tissues were measured at various time-points. In the CCl₄ group, the plasma aspartate aminotransferase (AST, 7694±3041IU/l)/alanine aminotransferase (ALT, 3241±2159 IU/l) levels peaked at 48 h after CCl₄ administration, but the other laboratory data did not differ significantly from the corresponding data in the controls. Centrilobular hepatocyte necrosis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells near the central vein area were observed via hematoxylin eosin (HE) and TUNEL staining, respectively, at 24 and 48 h after CCl₄ administration. Compared to the control group, the CCl₄ group did not show significantly the increased circulating TNF-α levels. But TNF-α levels in the liver tissues first peaked at 1h (5261±2253 pg/g liver), and a second peak was observed at 12h (3806±533 pg/g liver) after CCl₄ administration. Compared to the control group, the CCl₄ group showed significantly increased circulating levels of both sTNF-R1 (797±121pg/ml) and sTNF-R2 (5696±626 pg/ml) 1h after CCl₄ administration. Since the hepatocyte apoptosis may be resulted from binding of TNF-α with TNF-R1 at 24h after administration, and consequently the circulating TNF-R2 level might be approximately 10-fold higher than the circulating TNF-R1 level. In conclusion, increased circulating levels of sTNF-R1 and -R2 potentially contribute to drug-induced liver injury, together with AST/ALT.
authors.affiliation: Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. Electronic address: ijiri@gly.oups.ac.jp.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ijiri
authors.affiliation: Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kato
authors.affiliation: Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Maiko
authors.initials: M
authors.lastname: Sadamatsu
authors.affiliation: Pharmacotherapy II, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Takano
authors.affiliation: Department of Pathology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Kidney Center, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka 546-0002, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Cardiovascular Pharmacotherapy and Toxicology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hayashi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000503:physiopathology*; D022781:Hepatocytes / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: Carbon tetrachloride (CCl(4)); Drug-induced liver injury (DILI); Soluble TNF-receptor 1 (sTNF-R1); Soluble TNF-receptor 2 (sTNF-R2); Tumor necrosis factor-α (TNF-α)