ToxSci Advance Access originally published online on September 8, 2008
Toxicological Sciences 2008 106(2):538-545; doi:10.1093/toxsci/kfn188
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Detection of Cell-Free, Liver-Specific mRNAs in Peripheral Blood from Rats with Hepatotoxicity: A Potential Toxicological Biomarker for Safety Evaluation
Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka 532-8686, Japan
1 To whom correspondence should be addressed at Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Fax: +81(6)6300-6918. E-mail: Miyamoto_Makoto{at}takeda.co.jp.
Received January 8, 2008; accepted September 1, 2008
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Abstract |
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To verify the concept that cell-free organ/tissue–specific mRNAs leaking from drug-damaged organs/tissues into peripheral blood could be toxicological biomarkers for identification of the target organs of drug toxicity, we attempted to detect liver-specific mRNAs in peripheral blood from rats with chemical-induced hepatotoxicity. We selected 
1-microglobulin/bikunin precursor (Ambp) and albumin mRNAs as tentative liver-specific biomarkers and successfully detected them by reverse transcription (RT)-PCR in peripheral blood 24 h after D-galactosamine HCl (D-gal) or acetaminophen administration. Moreover, albumin mRNA was detected 2 h after D-gal administration, although plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were still unchanged. On the other hand, in peripheral blood from rat with bupivacaine HCl–induced skeletal muscle damage, neither Ambp nor albumin mRNA was detectable while plasma creatine kinase, ALT, and AST levels prominently increased 2 or 12 h after dosing. Furthermore, Ambp mRNA was also detectable in filtered plasma from rats with liver damage, indicating that cell-free Ambp mRNA can be present in peripheral blood. In conclusion, cell-free, liver-specific Ambp, and albumin mRNAs were detectable in peripheral blood from rats with chemical-induced liver damage. It is believed that the detection of cell-free organ/tissue–specific mRNA in peripheral blood is a promising approach in the survey of toxicological biomarkers.
Key Words: biomarker; cell free; hepatotoxicity; liver-specific mRNA; peripheral blood; rat.