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Serum amyloid A upsurge precedes standard biomarkers of hepatotoxicity in ritodrine-injected mice.

Abstract
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.
AuthorsHiroyoshi Tsuchiya, Junji Sato, Hidetoshi Tsuda, Yoko Fujiwara, Toshiyuki Yamada, Akio Fujimura, Taka-Aki Koshimizu
JournalToxicology (Toxicology) Vol. 305 Pg. 79-88 (Mar 08 2013) ISSN: 1879-3185 [Electronic] Ireland
PMID23370008 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Biomarkers
  • Serum Amyloid A Protein
  • Tocolytic Agents
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Adenylyl Cyclases
  • Ritodrine
Topics
  • Adenylyl Cyclases (metabolism)
  • Alanine Transaminase (blood)
  • Animals
  • Aspartate Aminotransferases (blood)
  • Biomarkers (blood)
  • Blotting, Western
  • Cell Line
  • Chemical and Drug Induced Liver Injury (blood)
  • Female
  • Immunoenzyme Techniques
  • Liver (chemistry, enzymology)
  • Mice
  • Mice, Inbred C57BL
  • Microarray Analysis
  • Real-Time Polymerase Chain Reaction
  • Ritodrine (toxicity)
  • Serum Amyloid A Protein (analysis, metabolism)
  • Tocolytic Agents (toxicity)

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