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

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.

Sample Treatment for Tissue Proteomics in Cancer, Toxicology, and Forensics

“…Its effects have been studied in their own right and it has also been used as a model system for DILI studies. An interesting recent paper [28] reports the study of acetaminophen-induced hepatotoxicity carried out using 18 18 O water, two atoms of 18 O are incorporated into the carboxyl terminus of each peptide generated in the digest. Comparative proteomic studies are performed by mixing the sample digest containing unlabelled peptides (generated in normal water) and with digest performed in the isotope-labelled water which contains 18 O peptides and analysing the resultant peptide pairs by mass spectrometry.…”

Toxicogenomics and New Advances in Toxicology

“…Örneğin; asetaminofenin neden olduğu karaciğer hasarının erken teşhisinde gen ifade değişikliğinin klinik öneminin olması gibi. 27 Toksikogenomik biyobelirteçler ("translasyonel biyobelirteç" olarak) ile klinik öncesi klasik toksisite çalışmalarında ortaya çıkmayan, ancak duyarlı hastalarda toksisiteye neden olma potansiyeline sahip olan ilaç adaylarının belirlenebileceği öngörülmektedir. 6,26…”

Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers

“…Although NSAIDs are some of the most commonly used medicines worldwide, they are associated with various adverse side effects which are generally dose related and represent a public health problem 5 . The use of NSAIDs has been associated with gastrointestinal injury, hepatotoxicity, renal and cardiovascular disorders and hypertension 6,7 . The NSAIDs benoxaprofen and bromfenac were withdrawn from the market due to severe hepatic toxicity 8,9 .…”