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ToxSci Advance Access published online on September 8, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn188
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Detection of Cell-Free, Liver-Specific mRNAs in Peripheral Blood from Rats with Hepatotoxicity: A Potential Toxicological Biomarker for Safety Evaluation.

Makoto Miyamoto, Mariko Yanai, Shingo Ookubo, Naoko Awasaki, Kenji Takami and Ryoetsu Imai

Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan

Corresponding author Makoto Miyamoto, Development Research Center, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. E-mail Miyamoto_Makoto{at}takeda.co.jp, TEL +81(6)6300-6937, FAX +81(6)6300-6918

Received January 8, 2008; revision received August 29, 2008; accepted September 1, 2008


  Abstract

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 {alpha}1-microglobulin/bikunin precursor (Ambp) and albumin mRNAs as tentative liver-specific biomarkers and successfully detected them by reverse-transcription polymerase chain reaction (RT-PCR) in peripheral blood 24 h after D-galactosamine HCl (D-gal) or acetaminophen (APAP) 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 (CK), 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.

Miyamoto_Makoto{at}takeda.co.jp, Yanai_Mariko{at}takeda.co.jp, Ookubo_Shingo{at}takeda.co.jp, Awasaki_Naoko{at}takeda.co.jp, Takami_Kenji{at}takeda.co.jp, Imai_Ryoetsu{at}takeda.co.jp


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