Highly expressed protein kinase A inhibitor α and suppression of protein kinase A may potentiate acetaminophen-induced hepatotoxicity

Jun Won Yun, Min Jeong Kim, Sung Dae Cho, Joo Young Lee, Ok Nam Bae, Kyung Min Lim

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Drug-induced hepatotoxicity is a serious adverse effect with high morbidity and mortality rates but substantial individual to individual variation is observed in its severity. Here we sought to discover factors determining the susceptibility to acetaminophen (APAP)-induced hepatotoxicity by comparing the global gene expression profile (27,342 genes) in pre-dose blood before APAP administration between susceptible and resistant animals ( N= 5) grouped based on the severity of hepatotoxicity. Forty-one genes were expressed differently (>1.5 fold change and p<. 0.05) between susceptible and resistant groups. Among them, protein kinase (cAMP-dependent) inhibitor alpha. , Pkia, a member of protein kinase A (PKA) inhibitor family, was found to be most significantly and highly expressed in susceptible animals (~3.5 fold with p<. 0.01). To investigate the effects of PKA inhibition on APAP-induced hepatotoxicity, we pre-treated H-89, a potent and selective inhibitor of PKA, prior to APAP administration in vivo. As a result, H-89 pretreatment significantly potentiated APAP-induced hepatotoxicity as determined by the increased serum alanine transaminase. These results were further corroborated by the exacerbation of APAP-induced glutathione depletion, suppression of antioxidant enzyme system, superoxide dismutase 1 and glutathione peroxidase 1, and peroxynitrite generation in the liver following H-89 pretreatment, reflecting that PKA may be involved in the protection against, or attenuation of APAP-induced hepatotoxicity, and Pkia can be employed to screen individuals susceptible to APAP-induced hepatotoxicity.

Original languageEnglish
Pages (from-to)59-65
Number of pages7
JournalToxicology Letters
Issue number1
StatePublished - 17 Aug 2014

Bibliographical note

Funding Information:
This work was supported by a grant from Hanyang University ( 201200000000204 ).


  • Acetaminophen
  • Hepatotoxicity
  • Individual variation
  • Protein kinase A
  • Toxicogenomics


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