Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury

Abstract

BackgroundAcetaminophen (APAP) is a commonly used analgesic. However, its use is associated with drug-induced liver injury (DILI). It is a prominent cause of acute liver failure, with APAP hepatotoxicity far exceeding other causes of acute liver failure in the United States. In order to improve its safe use this study aimed to identify individuals at risk for DILI prior to drug treatment by searching for non-genetic serum markers in healthy subjects susceptible to APAP-induced liver injury (AILI).MethodsHealthy volunteers (n = 36) received either placebo or acetaminophen at the maximum daily dose of 4 g for 7 days. Blood samples were taken prior to and after APAP treatment. Serum proteomic profiling was done by 2D SDS-PAGE and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Additionally, the proteins C-reactive protein, haptoglobin and hemopexin were studied by quantitative immunoassays.ResultsOne-third of study subjects presented more than four-fold increased alanine transaminase activity to evidence liver injury, while serum proteomics informed on 20 proteins as significantly regulated. These function primarily in acute phase and immune response. Pre-treatment associations included C-reactive protein, haptoglobin isoforms and retinol binding protein being up to six-fold higher in AILI susceptible individuals, whereas alpha1-antitrypsin, serum amyloid A, kininogen and transtyretin were regulated by nearly five-fold in AILI responders. When compared with published findings for steatohepatitis and cases of hepatocellular, cholestatic and mixed DILI, 10 proteins were identified as uniquely associated with risk for AILI, including plasminogen. Notably, this zymogen facilitates macrophage chemotactic migration and inflammatory response as reported for plasminogen-deficient mice shown to be resistant to APAP hepatotoxicity. Finally, analysis of a publicly available database of gene expression profiles of cultures of human hepatocytes treated with drugs labeled as no- (n = 8), low- (n = 45) or most-DILI-concern (n = 39) confirmed regulation of the identified biomarkers to demonstrate utility in predicting risk for liver injury.ConclusionsThe significant regulation of acute phase reactants points to an important link between AILI and the immune system. Monitoring of serum acute phase reactants prior to drug treatment may contribute to prevention and management of AILI, and may also be of utility for other drugs with known liver liabilities.

Co-culture of Hepatocytes and Kupffer Cells as an In Vitro Model of Inflammation and Drug-Induced Hepatotoxicity

“…29,37 The compounds were tested over a 48-h exposure period at several concentrations that were relevant to their exposure in vivo or that had been shown to cause hepatocellular injury in vitro. We then examined their immune-mediated (LPS induced) and direct effects (without LPS) on the production of key cytokines, namely TNF-α and IL-6, and metabolic capacity as represented by Cyp3A activity.…”

“…Notably, APAP is another compound known to be associated with immune-mediated enhanced hepatotoxic events leading to severe liver injury and liver failure in some individuals. 37 Although it is well established in the literature that APAP is metabolically activated to a reactive metabolite (N-acetyl-p-benzoquinone imine), which depletes glutathione as a key initiating event leading to oxidative stress and hepatocellular injury, our results provide confirmation that there may be secondary pathways involved in its hepatotoxic mechanism, such as changes in cytokine profiles and metabolic capacity, that may be responsible for enhancement of toxicity in LPS-activated HKCCs, outside the classical APAP-induced cytotoxic effects from N-acetyl-p-benzoquinone imine, formation. Notably, the “idiosyncratic” nature of the severity of APAP toxicity in some patients has been linked to the patient's adaptive immune responses, suggesting that it too may fall into a category of a “TVX-like” mechanism.…”

“…Notably, the “idiosyncratic” nature of the severity of APAP toxicity in some patients has been linked to the patient's adaptive immune responses, suggesting that it too may fall into a category of a “TVX-like” mechanism. 15,37 …”

Biochemical markers of the functional liver state in rats with toxic hepatitis under the conditions of germanium citrate administration

“…Екзогенно-токсичне уражен-ня печінки виникає внаслідок впливу низки різноманітних фізичних і хімічних факторів, серед яких -медикаментозні препарати, ал-коголь, засоби побутової хімії, токсини гри-бів тощо [2,9]. На сьогодні токсичні гепатити становлять одну з найсерйозніших медико-соціальних проблем у світі, що зумовлено не тільки високим рівнем захворюваності серед населення, але й суттєвими економічними за-тратами на діагностичний пошук та лікуван-ня [1,4,6,18].…”

Activity of liver mitochondrial NAD+-dependent dehydrogenases of the krebs cycle in rats with acetaminophen-induced hepatitis developed under conditions of alimentary protein deficiency

“…Показано, что нарушения работы системы энергообеспечения выступают вторичным звеном патогенеза ряда заболеваний [4]. Учитывая рост числа регистрируемых побочных (токсических) эффектов лекарственных препаратов и зависимость функциональной активности печени от эффективности работы системы энергообеспечения гепатоцитов [5,6], исследование механизмов, определяющих развитие энергетического дисбаланса, особенно актуально. В контексте изучения биохимических механизмов нарушения функций печени при лекарственных или токсических гепатитах [7], удобным модельным токсином является ацетаминофен, который широко применяется в медицинской практике в качестве анальгетического и пиральгетического средства, а в случае передозировки вызывает существенные повреждения центральнолобулярных областей печени [8].…”