Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury

Kenneth H. Davis; R. E. Folsom; F. Ivy Carroll; Phillip C. Cooley; Lyle M. Retzlaff; Michael F. Weeks; H. Koo; Herbert H. Seltzman; E. Pellizzari; Deborah W. McFadden; Roger D. Austin; Martin B. Lee; Judith T. Lynch; Debra M. Fleischmann; Carol Place; Stephen D. Cooper; Rick L. Williams; Lillie B. Barber; Doris J. Rouse; Ivey A. McDaniel; Charlotte O. Scheper; Paul Kizakevich; Donna M. Jewell; Marion E. Deerhake; Cora B. Parker; Eugene P. Brantly; Phyllis D. Elkins; Patricia A. Cunningham; Robert S. Truesdale; Sara C. Wheeless; Robert M. Bray; Cynthia A. Salmons; Gary B. Howe; Coleen M. Northeim; Susan K. Myers; Gordon M. Cressman; Josephine A. Mauskopf; Tim J. Gabel; Luis Arturo Crouch; Celia D. Keller; Lisa E. Packer; Pamela B. Lamb; Keith White Little; Nathaniel F. Rodman; M. Owen; James P. Hayes; Daniel L. Winfield; Deborah A. Gibbs; Janice E. Kelly-Reid; Wayne G. Winstead; Cindy O. McClintock; Terrence K. Pierson; Johnny R. Albritton; Sherry L. Black; Jeffrey B. Coburn; Joe B. Simpson; Ed E. Rickman; James T. Hanley; R. Suresh; Barbara L. Kroner; K. Heller; James C. Blake; Barri B. Burrus; Anthony C. Clayton; Donna S. Womack; S. Mascarella; Scott A. Guthrie; Sheryl C. Cates; Albert D. Bethke; Suson F. VonLehmden; Kathryn L. Dowd; Daniel J. Pratt; Lisa J. McQuay; Matthew A. Koch; Jonathan T. Ennis; Robert A. Zerbonia; Nick L. Kinsey; Susan H. Kinsey; Christopher P. Carson; J. Newsome; S. Keesling; James A. O'Rourke; Kathryn R. Batts; Craig R. Hollingsworth; Priya Suresh; Joseph Wendell Wilson; Vorapranee Wickelgren; E. Andrew Jessup; Diana S. Goss; Sheri E. Fehnel; Gayle S. Bieler; Donna P. Coleman; R. Crawford; Jeanne Ann Snodgrass; Nellie I. Hansen; Michelle Lang; Deirdre M. Mladsi; Gary A. Zarkin; Rachel A. Caspar; Carol L. Woodell; Yuan Gao; Zhijun Cao; Xi Yang; Mohamed A. Abdelmegeed; Jinchun Sun; Si Chen; Richard D. Beger; Kelly Davis; William F. Salminen; Byoung-Joon Song; Donna L. Mendrick; Li-Rong Yu

Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury

Gao, Y., Cao, Z., Yang, X., Abdelmegeed, M. A., Sun, J., Chen, S., Beger, R. D., Davis, K., Salminen, W. F., Song, B-J., Mendrick, D. L., & Yu, L-R. (2017). Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury. Proteomics. Clinical Applications, 11(1-2). https://doi.org/10.1002/prca.201600123

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Abstract

Purpose: Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury.

Experimental design: Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS.

Results: Molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose-and time-dependent manner upon APAP treatment. Imbalanced expression of hemeoxygenase 1 (HMOX1) and biliverdin reductase A (BLVRA) was associated with hepatotoxicity. Protein abundance changes of a total of 31 proteins were uniquely correlated to liver damage, among which a dramatic increase of HMOX1 levels in plasma was observed. Liver injury-associated significant elevation of plasma HMOX1 was further validated in mice treated with APAP.

Conclusions and clinical relevance: This study unveiled molecular changes associated with APAP-induced liver toxicity at the pathway levels and identified HMOX1 as a potential plasma biomarker of liver injury.