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.