Abstract
Acetaminophen is a widely prescribed drug used to relieve pain and fever; however, it is a leading cause of drug-induced liver injury and a burden on public healthcare. In this study, hepatotoxicity in mice post oral dosing of acetaminophen was investigated using liver and sera samples with Fourier Transform Infrared microspectroscopy. The infrared spectra of acetaminophen treated livers in BALB/c mice show decrease in glycogen, increase in amounts of cholesteryl esters and DNA respectively. Rescue experiments using L-methionine demonstrate that depletion in glycogen and increase in DNA are abrogated with pre-treatment, but not post-treatment, with L-methionine. This indicates that changes in glycogen and DNA are more sensitive to the rapid depletion of glutathione. Importantly, analysis of sera identified lowering of glycogen and increase in DNA and chlolesteryl esters earlier than increase in alanine aminotransferase, which is routinely used to diagnose liver damage. In addition, these changes are also observed in C57BL/6 and Nos2 −/− mice. There is no difference in the kinetics of expression of these three molecules in both strains of mice, the extent of damage is similar and corroborated with ALT and histological analysis. Quantification of cytokines in sera showed increase upon APAP treatment. Although the levels of Tnfα and Ifnγ in sera are not significantly affected, Nos2 −/− mice display lower Il6 but higher Il10 levels during this acute model of hepatotoxicity. Overall, this study reinforces the growing potential of Fourier Transform Infrared microspectroscopy as a fast, highly sensitive and label-free technique for non-invasive diagnosis of liver damage. The combination of Fourier Transform Infrared microspectroscopy and cytokine analysis is a powerful tool to identify multiple biomarkers, understand differential host responses and evaluate therapeutic regimens during liver damage and, possibly, other diseases.
Highlights
Drug-induced hepatotoxicity has been attributed to be the cause for a major percentage of patient morbidity and mortality
This study focuses on finding novel markers using Fourier Transform Infrared (FTIR) imaging which, coupled with cytokine responses, will be helpful for rapid diagnosis and better understanding of host responses during liver damage
There are three aspects to this study involving oral dosing of mice, the physiological route of entry, with APAP: First is the feasibility of using FTIR spectroscopy to diagnose APAP induced liver toxicity with high sensitivity using liver samples or sera
Summary
Drug-induced hepatotoxicity has been attributed to be the cause for a major percentage of patient morbidity and mortality. Acetaminophen (APAP) is an analgesic and antipyretic drug which is extensively used for therapeutic purposes. The probability of developing liver injury due to consumption of APAP as prescribed is low; APAP consumption with alcohol, during fasting and malnutrition for prolonged periods may trigger hepatotoxicity. Accidental and intentional over dosing of APAP is a cause of major health concern as it is the main source of acute liver failure in the Western world. Suspected APAP hepatotoxicity can be effectively treated with N-acetylcysteine, yet an estimated 500 patients die each year in the USA [1,2]. There is a need to better understand, diagnose and effectively treat cases of APAP-induced hepatotoxicity
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