Identification of novel liver-specific mrnas in plasma for biomarkers of drug-induced liver injury and quantitative evaluation in rats treated with various hepatotoxic compounds

Shingo Okubo, Makoto Miyamoto, Kenji Takami, Masayuki Kanki, Atsushi Ono, Noriyuki Nakatsu, Hiroshi Yamada, Yasuo Ohno, Tetsuro Urushidani

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Circulating liver-specific mRNAs such as albumin (Alb) and α-1-microglobulin/bikunin precursor (Ambp) have been reported to be potential biomarkers for drug-induced liver injury (DILI). We identified novel circulating liver-specific mRNAs and quantified them, together with the two previously reported mRNAs, in plasma from rats treated with various hepatotoxicants to validate circulating liver-specific mRNAs as biomarkers for DILI. Among six genes selected from the database, high liver specificity of apolipoprotein h (Apoh) and group-specific component (Gc) mRNAs were confirmed by reverse transcription (RT)-PCR and the copy numbers of these mRNAs elevated in plasma from rats treated with thioacetamide. Liver-specific mRNAs (Alb, Ambp, Apoh, and Gc) were quantified by real-time RT-PCR in plasma from rats with single dosing of seven hepatotoxicants. There were noticeable interindividual and intercompound variabilities in the severity of liver injury. The levels of four mRNAs increased almost in parallel and correlated with changes in the alanine aminotransferase (ALT) values and the hepatocellular necrosis scores at 24 h after dosing. It was noteworthy that the magnitude of the increases in mRNA levels was greater than that in the ALT value. Time course analysis within 24 h after dosing revealed that the timing of the increase was different among mRNA species, and the plasma levels of Alb and Gc mRNAs increased substantially earlier than the ALT values, suggesting that patterns of changes in circulating liver-specific mRNAs indicate the progression of liver injury. These results strongly support the reliability and usefulness of the four circulating liver-specific mRNAs as biomarkers for DILI.

Original languageEnglish
Pages (from-to)21-31
Number of pages11
JournalToxicological Sciences
Volume132
Issue number1
DOIs
Publication statusPublished - Mar 2013
Externally publishedYes

Fingerprint

Chemical and Drug Induced Liver Injury
Biomarkers
Liver
Rats
Plasmas
Messenger RNA
Pharmaceutical Preparations
Alanine Transaminase
Albumins
Apolipoproteins
Transcription
Reverse Transcription
Thioacetamide
Polymerase Chain Reaction
Wounds and Injuries
Serum Albumin

Keywords

  • Biomarker
  • Circulating liver-specific mrnas
  • Drug-induced liver injury
  • Hepatotoxic compounds
  • Quantitative analysis

ASJC Scopus subject areas

  • Toxicology

Cite this

Identification of novel liver-specific mrnas in plasma for biomarkers of drug-induced liver injury and quantitative evaluation in rats treated with various hepatotoxic compounds. / Okubo, Shingo; Miyamoto, Makoto; Takami, Kenji; Kanki, Masayuki; Ono, Atsushi; Nakatsu, Noriyuki; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro.

In: Toxicological Sciences, Vol. 132, No. 1, 03.2013, p. 21-31.

Research output: Contribution to journalArticle

Okubo, Shingo ; Miyamoto, Makoto ; Takami, Kenji ; Kanki, Masayuki ; Ono, Atsushi ; Nakatsu, Noriyuki ; Yamada, Hiroshi ; Ohno, Yasuo ; Urushidani, Tetsuro. / Identification of novel liver-specific mrnas in plasma for biomarkers of drug-induced liver injury and quantitative evaluation in rats treated with various hepatotoxic compounds. In: Toxicological Sciences. 2013 ; Vol. 132, No. 1. pp. 21-31.
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