Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
➤ Gửi thông báo lỗi ⚠️ Báo cáo tài liệu vi phạmNội dung chi tiết: Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2a’Ow* of Mwrorab®: TcwobjyAlAi’«ni!yo/Xdns« MraWCeMer. Kanxn City. Ki USACHAPTER MENU23.1Introduction, 37323.2Acetaminophen Overdose as a Model for Biomarker Discovery, 37323.3Acetaminophen Overdose: Mechanisms of Toxicity in Mice ai>d37423.48Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
development and in clinical trials. In addition, idiosyncratic hepatotoxicity leads to black box warnings or even withdrawal of approved drugs from t37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2fficiently sensitive to detect dose-dependent hepatotoxins, there are no biomarkers available that could alert to a potential idiosyncratic toxicity. Clinically, acetaminophen (APAP) overdose remains the most common source of both drug-induced liver injury and acute liver failure (ALF) (Lee, 2013). Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2Patients that develop ALF have a very poor outcome, with mortality up to 50% (Lee, 2013). Early identification of which patients will proceed to ALE iEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
s critical, as these patients can be treated more aggressively or listed for transplantation earlier. As such, biomarkers of patient outcome are of co37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2ransplant and which patients will recover spontaneously.The best biomarkers are those that are also informative of the mechanisms at play in the pathophysiology or valuable clinically due to prognostic capacity. Biomarkerspresent in the serum or urine of patients are of the most interest and the gre Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2atest use. Many of these serum and urine biomarkers have a single point of origin in tissue and thus accurately reflect what is happening in these tisEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
sues, in a mechanistic fashion, without the need for biopsy. A number of these “mechanistic biomarkers" have recently been a source of focus in the li37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2Gill and laeschke, 2014; Beger et al., 2015). Release of many of these mechanistic biomarkers can be traced back to damage of the mitochondria, and thus considerable progress has recently been made in the field of biomarkers of mitochondrial damage. The purpose of this chapter will be to define thes Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2e markers and discuss their clinical viability and basic science relevance with regard to the murine APAP hepatotoxicity model and human patients withEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
APAP overdose.23.2Acetaminophen Overdose as a Model for Biomarker DiscoveryA number of mitochondrial biomarkers have been established for liver disea37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2drial Dysfunction Canted by Drttp and Environmental Toxieanti. Volume I. First Edition. Edited by Yvonne Will and lames A. Dykens. © 2018 John Wiley & Sons, Inc. Published 2018 by lohn Wiley & Sons. Inc.3 74 I MKoờìondrtal ữyitưixtiữn tv Drug and Environmental ỉoxtcantĩfur biomarker discovery for a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2number of reasons: (i) it is technically simple and highly repeatable, (ii) the mechanisms associated with the model are largely well delineated. andEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
(iii) it is a clinically relevant murine model with high fidelity to the human condition (McGill cl al., 2012; laeschke et al., 2014, Jaeschke, 2015).37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2w of the understood meclianisms of A PAI1 (for a more complete, updated overview: Ramachandran and Jaeschke, 2017; Woolbright and Jacschke, 2017), but rather a version focused on the pathology associated with the mitochondria.23.3Acetaminophen Overdose: Mechanisms of Toxicity in Mice and Man23.3.1Dr Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2ug Metabolism and Protein AdductsAPAP is an over-the-counter analgesic and antipyretic. Normally, greater than 85% of an APAP dose is conjugated to eiEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
ther UDP'glucuronide or sulfate and excreted via phase II metabolism (McGill and Jaeschke, 2013). Therapeutic doses are safe; however, an overdose of 37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2 (NAPQ1) (Dahlin et al., 1984), which is a reactive electrophile that covalently adducts cellular proteins causing oxidative stress in the cell (Dahlin et al., 1984) and is largely detoxified through a spontaneous reaction with the endogenous antioxidant glutathione (GSH) (Mitchell et al., 1973). Th Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2is results in the depletion of cellular GS11 levels in the liver. GSII depletion is currently used as a hallmark for measuring A PAP metabolic activatEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
ion experimentally (McGill and Jaeschke, 2013). I he interaction between NAPQI and GS11 is also the basis lor the current gold- standard therapeutic, 37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2 reactive oxygen and peroxynitrite (Knight et al.. 2(X)2). During this metabolism and GSH depletion, NAPQI begins to adduct sulfhydryl groups on proteins forming acetaminophen cysteine (APAP CYS) adducts (Pumford el al., 1989), which have been proposed as a diagnostic indicator of APAP overdose in p Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2atients (Roberts et al., 2017). levels above 1 pM of APAP CYS in scrum arc associated with liver toxicity, although recent data indicate APAP-CYS adduEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
cts may be released even at therapeutic doses when patients do not have any liver toxicity (Heard et al., 2011;McGill el al., 2013). In addition, whil37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2in human hepatocytes (Xie et al., 2014). As a result, early-presenting patients (<8h after A PAP overdose) show very low adduct levels in serum compared with late-presenting patients despite that both groups look a massive overdose (Xie cl al., 2015a). Thus, serum adduct levels can be important biom Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2arkers to diagnose specifically A PAP overdose, but the time of exposure needs to be considered when interpreting the data.23.3.2Critical Role of MitoEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
chondria In APAP HepatotoxicityMitochondria emerged as central players in the intracellular signaling events of APAP-induced cell death. First, it was37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2itochondrial adducts and causes toxicity in mice (Tirmenstein and Nelson, 1989). However, AMAP forms mitochondrial adducts in human hepatocytes and causes toxicity (Xie et al., 2015b). Protein adduct formation impairs the mitochondrial respiratory chain (Meyers et al., 1988) and triggers a selective Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2 oxidant stress (laeschke, 1990) and peroxynitrite formation inside mitochondria (Cover et al., 2005). Some of these reactive oxygen species escape inEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
to the cytosol and trigger the activation of a mitogen-activated protein kinase cascade, which ultimately leads to c-|un-Ar-terniinal kinase (INK) act37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2rhe amplified oxidant stress and peroxynitrite formation leads to the opening of the mitochondrial membrane permeability transition pore (MPTP), which causes the collapse of the membrane potential and cessation of ATP synthesis (Kon cl al., 2004; LoGuidice and Boclslcrli, 2011; Ramachandrail cl aL, Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 22011a). The MPTP opening also triggers matrix swelling and rupture of the outer mitochondrial membrane, which releases intermembrane proteins such asEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
apoptosis-inducing factor (AID and endonuclease G both of which translocate to the nucleus and induce DNA fragmentation (Bajt et al, 2006). The mitoch37323Biomarkers of Mitochondrial Injury After Acetaminophen Overdose: Glutamate Dehydrogenase and BeyondBenjamin L. Woolbnght and Hartmut JaeichkeOn’a Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2ria in Al’AI’ hepatotoxicity has been supported by many different experimental approaches. In addition to the direct evidence of a mitochondrial oxidant stress and peroxynitrite formation inside of mitochondria (Jaeschke, 1990; Cover et al., 200.5), scavenging oftHomcưterỉ of Mitochondria! Injury Af Ebook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2ter Acetaminophen Overdose. Glutamate Dehydrogenase and tleyond 375these oxidants bv mitochondrial GS11 is highly protective (Knight et al., 2002; SaiEbook Mitochondrial dysfunction caused by drugs and environmental toxicants (Vol 1): Part 2
to el ill-. 2010). In addition, preventing peroxynitrite formation by accelerated dismutation of superoxide through mito- TEMPO, a mitochondria- targeGọi ngay
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