title: Characterization of release profile of ornithine carbamoyltransferase from primary rat hepatocytes treated with hepatotoxic drugs: Implications for its unique potential as a drug-induced liver injury biomarker.
abstract: Ornithine carbamoyltransferase (OCT) is a mitochondrial protein expressed primarily in the liver. It has been shown that, like alanine aminotransferase (ALT), OCT is released from damaged hepatocytes in rats and humans, which has given rise to the possibility that OCT might provide a diagnostic biomarker of various forms of liver damage, including drug-induced liver injury (DILI). However, OCT release characteristics in DILI, as well as their diagnostic advantages, remain elusive. Therefore, this study aimed at clarifying whether and how OCT is released from rat primary hepatocytes in vitro using seven potentially hepatotoxic drugs. The results showed that OCT releases from damaged hepatocytes were observed for all tested drugs, and that those releases were not associated with mitochondrial membrane proteins. It should be underscored that the release dynamics were significantly larger than those of ALT. Furthermore, unlike ALT, the maximum OCT release levels showed differences depending on the drug being tested, suggesting that OCT release was susceptible to toxicity mechanisms. Taken together, these unique release characteristics highlight the possibility that OCT could provide a promising DILI biomarker that might contribute not only to diagnostic accuracy improvements, but also to a better understanding of toxicity types in clinical and drug development settings.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan. Electronic address: tomomif@faculty.chiba-u.jp.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Furihata
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Aizawa
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Koibuchi
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Meiyan
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamasaki
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Minaka
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba 260-8675, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D009954:Ornithine Carbamoyltransferase / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015415:Biomarkers; D009954:Ornithine Carbamoyltransferase; D000410:Alanine Transaminase
keywords: Biomarker; Drug development; Drug-induced liver injury; Hepatocytes; Liver; Mitochondria; Ornithine carbamoyltransferase; Toxicity