Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice.
The tocolytic agent ritodrine acts on the β2-adrenoceptor and is an effective treatment option for preterm labor. However, several adverse effects of ritodrine therapy, including liver damage, have been noted. To elucidate the underlying mechanisms of ritodrine-induced adverse effects, development of sensitive biomarkers of these adverse events is necessary. Here, we report the development and analysis of an animal model of ritodrine-induced liver damage. Female mice received daily ritodrine injections for 2 weeks; liver samples were then collected and subjected to DNA microarray analysis. Ritodrine significantly altered the expression of genes related to steroid and lipid metabolism, as well as the metabolism of ritodrine itself. Importantly, expression of the acute-phase reactant serum amyloid A (SAA) significantly increased after ritodrine injection, with values indicating the largest fold-change. This large increase in blood SAA levels serves as a more sensitive biomarker than conventional liver enzymes, such as aspartate aminotransferase and alanine aminotransferase. The increase in SAA expression is specific to ritodrine-induced liver damage, because SAA expression was not induced by other hepatotoxic drugs such as acetaminophen, valproic acid, or metformin. Our in vitro studies showed that cyclic adenosine 3',5'-monophosphate (cAMP) accumulation was not a primary cause of the ritodrine-induced SAA increase. Instead, SAA expression was enhanced by indirect phosphorylation of the signal transducer and activator of transcription-3 (STAT3) mediated by interleukin-6. Therefore, our study provides a method for sensitive and early detection of hepatic injury, and may thus help preclude serious liver damage due to ritodrine use in preterm labor.
Division of Molecular Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan.
Hiroyoshi
H
Tsuchiya
Junji
J
Sato
Hidetoshi
H
Tsuda
Yoko
Y
Fujiwara
Toshiyuki
T
Yamada
Akio
A
Fujimura
Taka-Aki
TA
Koshimizu
D000262:Adenylyl Cyclases / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood*; D005260:Female; D007124:Immunoenzyme Techniques; D008099:Liver / Q000737:chemistry / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D012312:Ritodrine / Q000633:toxicity*; D000685:Serum Amyloid A Protein / Q000032:analysis / Q000378:metabolism*; D015149:Tocolytic Agents / Q000633:toxicity*
D015415:Biomarkers; D000685:Serum Amyloid A Protein; D015149:Tocolytic Agents; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000262:Adenylyl Cyclases; D012312:Ritodrine