Gene expression profiling in rat liver treated with various hepatotoxic-compounds inducing coagulopathy.
A large-scale transcriptome database of rat liver (TG-GATEs) has been established by the Toxicogenomics Project in Japan. In the present study, we focused on 8 hepatotoxic compounds within TG-GATEs, i.e., clofibrate, omeprazole, ethionine, thioacetamide, benzbromarone, propylthiouracil, Wy-14,643 and amiodarone, which induced coagulation abnormalities. Aspirin was selected as a reference compound that directly causes coagulation abnormality, but not through liver toxicity. In blood chemical examinations, for all the coagulopathic compounds there was little elevation of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), suggesting no severe cell death by treatment with the compounds. We extracted 344 probe sets from the data for these 8 typical drugs, which induced this phenotype at any time from 3 to 28 days of repeated administration. Principal component analysis using these probe sets clearly separated dose- and time-dependent clusters of the treated groups from their controls, except aspirin and propylthiouracil, both of which were considered to cause coagulopathy not due to their hepatotoxicity but due to their direct effects on the blood coagulation system. Reviewing the extracted genes, changes in lipid metabolism were found to be dominant. Genes related to blood coagulation were generally down-regulated by these drugs except that vitamin K epoxide reductase complex subunit 1 (Vkorc1) like 1, a paralogous gene of Vkorc1, was up-regulated. As expected, expression changes of these genes were least prominent in aspirin or propylthiouracil-treated liver. We concluded that these probe sets could be a good starting point in developing mechanism-based biomarkers for diagnosis or prognosis of hepatotoxicity-related coagulation abnormalities in the early stage of drug development.
Hirode
Mitsuhiro
M
Toxicogenomics Project, National Institute of Biomedical Innovation, Osaka.
Omura
Ko
K
Kiyosawa
Naoki
N
Uehara
Takeki
T
Shimuzu
Toshinobu
T
Ono
Atsushi
A
Miyagishima
Toshikazu
T
Nagao
Taku
T
Ohno
Yasuo
Y
Urushidani
Tetsuro
T
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000925:Anticoagulants / Q000145:classification / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D001778:Blood Coagulation Disorders / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043922:Toxicogenetics; D015262:Xenobiotics / Q000145:classification / Q000633:toxicity*
D000925:Anticoagulants; D015415:Biomarkers; D015262:Xenobiotics; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase