Effects of fenofibrate on plasma and hepatic transaminase activities and hepatic transaminase gene expression in rats.
Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are widely used as sensitive markers of possible tissue damage, particularly liver toxicity. Lipid-lowering drugs, such as fibrates, slightly increase serum transaminase levels in humans, but there is little evidence that the phenomenon is related to drug-induced liver injury (DILI). Some in vitro studies have indicated that the elevations of serum transaminase activities after treatment of humans with fenofibrate, one of the fibrates, are related to increased transaminase synthesis in the hepatocytes rather than to transaminase leakage from the hepatocytes associated with cell lysis. In this study, male F344/DuCrlCrlj (Fischer) rats were treated once with fenofibrate at a dose level of 400 mg/kg and the relationships between the pharmacological effects, blood and hepatic transaminase activities and the gene expression of the transaminases in the liver were investigated. Fenofibrate treatment slightly increased plasma transaminase activities in rats with the findings directly related to the pharmacological action of the drug. The increases were in parallel with increases in hepatic transaminase activities associated with increases in the transaminase genes in the liver and were not considered to be a consequence of hepatotoxicity from the drug. The modification in transaminase gene expression is likely to be secondary to the pharmacological action of fenofibrate. The evidence obtained in our study underlines the importance of gene regulation as a possible alternative mechanism for increased blood transaminase activities.
Kobayashi
Akio
A
Toxicology Research Lab., Central Pharmaceutical Research Institute, JAPAN TOBACCO INC., Kanagawa 257-0024, Japan. akio.kobayashi@jt.com
Suzuki
Yusuke
Y
Kuno
Hideyuki
H
Sugai
Shoichiro
S
Sakakibara
Hiroyuki
H
Shimoi
Kayoko
K
D000410:Alanine Transaminase / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology* / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D011345:Fenofibrate