title: Highly expressed protein kinase A inhibitor α and suppression of protein kinase A may potentiate acetaminophen-induced hepatotoxicity.
abstract: 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.
authors.affiliation: Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Yun
authors.affiliation: College of Pharmacy, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-808, Republic of Korea.
authors.forename: MinJeong
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Oral Pathology, School of Dentistry and Institute of Oral Bioscience, Chonbuk National University, Jeon-ju, Republic of Korea.
authors.forename: Sung-Dae
authors.initials: SD
authors.lastname: Cho
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon, Republic of Korea.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Institute of Pharmaceutical Sciences, Hanyang University, Ansan, Gyeonggido 426-791, Republic of Korea. Electronic address: onbae@hanyang.ac.kr.
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Ewha Womans University, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 120-808, Republic of Korea. Electronic address: kmlim@ewha.ac.kr.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009569:Nitric Oxide / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; C107593:Pkia protein, mouse; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D009569:Nitric Oxide; D000082:Acetaminophen; D012313:RNA; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D017868:Cyclic AMP-Dependent Protein Kinases; D005978:Glutathione; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
keywords: Acetaminophen; Hepatotoxicity; Individual variation; Protein kinase A; Toxicogenomics