Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes.

Burcham, Philip; Harman, Andrew W.

doi:10.1016/s0021-9258(19)67754-9

Cited by 197 publications

(34 citation statements)

References 30 publications

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“…57 Our results are in line with previous studies that reported a decrease in GSH levels upon APAP treatment in animal models and in cell cultures. 56,58,59,[60][61][62][63][64][65] However, the time and amplitude of decreases varied with cell lines and the animal models used for these studies. In addition to a decrease in GSH, increases in intracellular GSSG have been reported during the recovery phase of cellular GSH content 50,66 after APAP treatment.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20] Furthermore, the exposure of mouse hepatocytes to NAPQI stimulated the mitochondrial dysfunction that was observed with APAP. 21 Uncoupling of cytochrome P-450 2E1 appears to be a significant mechanism that leads to increased reactive oxygen species (ROS) in APAP toxicity. The superoxide anion, thus formed, dismutates to hydrogen peroxide 22 and eventually forms highly reactive hydroxyl radicals which may, in turn, oxidize lipids that lead to initiation of lipid peroxidation as well as oxidation of proteins and nucleic acids.…”

Section: Introductionmentioning

confidence: 99%

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Comparative evaluation of N-acetylcysteine and N-acetylcysteineamide in acetaminophen-induced hepatotoxicity in human hepatoma HepaRG cells

Tobwala

Khayyat

Fan

et al. 2014

Exp Biol Med (Maywood)

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Acetaminophen (N-acetyl-p-aminophenol, APAP) is one of the most widely used over-the-counter antipyretic analgesic medications. Despite being safe at therapeutic doses, an accidental or intentional overdose can result in severe hepatotoxicity; a leading cause of drug-induced liver failure in the U.S. Depletion of glutathione (GSH) is implicated as an initiating event in APAP-induced toxicity. N-acetylcysteine (NAC), a GSH precursor, is the only currently approved antidote for an APAP overdose. Unfortunately, fairly high doses and longer treatment times are required due to its poor bioavailability. In addition, oral and intravenous administration of NAC in a hospital setting are laborious and costly. Therefore, we studied the protective effects of N-acetylcysteineamide (NACA), a novel antioxidant, with higher bioavailability and compared it with NAC in APAP-induced hepatotoxicity in a human-relevant in vitro system, HepaRG. Our results indicated that exposure of HepaRG cells to APAP resulted in GSH depletion, reactive oxygen species (ROS) formation, increased lipid peroxidation, mitochondrial dysfunction (assessed by JC-1 fluorescence), and lactate dehydrogenase release. Both NAC and NACA protected against APAP-induced hepatotoxicity by restoring GSH levels, scavenging ROS, inhibiting lipid peroxidation, and preserving mitochondrial membrane potential. However, NACA was better than NAC at combating oxidative stress and protecting against APAP-induced damage. The higher efficiency of NACA in protecting cells against APAP-induced toxicity suggests that NACA can be developed into a promising therapeutic option for treatment of an APAP overdose.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparative evaluation of N-acetylcysteine and N-acetylcysteineamide in acetaminophen-induced hepatotoxicity in human hepatoma HepaRG cells

Tobwala

Khayyat

Fan

et al. 2014

Exp Biol Med (Maywood)

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“…Calcium alterations and oxidative stress in mitochondria have also been reported (Tirmenstein and Nelson 1989;Jaeschke 1990). Moreover, inhibition of activity at complexes I and II, but not at complex III, were reported in isolated rat hepatocytes (Burcham and Harman 1991) and in vivo (Donnelly et al 1994). Also, ATP levels decrease in vivo and in treated hepatocytes (Burcham and Harman 1991;Halmes et al 1995;Vendemiale et al 1996;Banerjee et al 2015;Banerjee et al 2017).…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 98%

“…Moreover, inhibition of activity at complexes I and II, but not at complex III, were reported in isolated rat hepatocytes (Burcham and Harman 1991) and in vivo (Donnelly et al 1994). Also, ATP levels decrease in vivo and in treated hepatocytes (Burcham and Harman 1991;Halmes et al 1995;Vendemiale et al 1996;Banerjee et al 2015;Banerjee et al 2017). Similar changes have been shown by adding NAPQI to hepatocytes (Andersson et al 1990).…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 98%

The development and hepatotoxicity of acetaminophen: reviewing over a century of progress

McGill

Hinson

2020

Drug Metabolism Reviews

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Acetaminophen (APAP) was first synthesized in the 1800s, and came on the market approximately 65 years ago. Since then, it has become one of the most used drugs in the world. However, it is also a major cause of acute liver failure. Early investigations of the mechanisms of toxicity revealed that cytochrome P450 enzymes catalyze formation of a reactive metabolite in the liver that depletes glutathione and covalently binds to proteins. That work led to the introduction of N acetylcysteine (NAC) as an antidote for APAP overdose. Subsequent studies identified the reactive metabolite N-acetyl-p-benzoquinone imine, specific P450 enzymes involved, the mechanism of P450-mediated oxidation, and major adducted proteins. The mechanisms downstream of metabolism remain poorly understood but several events appear critical. These events include development of an initial oxidative stress, reactive nitrogen formation, altered calcium flux, JNK activation and mitochondrial translocation, inhibition of mitochondrial respiration, the mitochondrial permeability transition, and nuclear DNA fragmentation. Additional research is necessary to fill remaining gaps in our knowledge of the toxicity, such as the source of the initial oxidative stress, and to improve our understanding liver regeneration after APAP overdose. A better understanding of these mechanisms may lead to additional treatment options. Even though NAC is an excellent antidote, its effectiveness is limited to the first 16 hours following overdose.

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“…Δημοσιεύθηκαν επίσης λειτουργικές μεταβολές στην ικανότητα απομάκρυνσης του ασβεστίου 837 . Επιπρόσθετα, τα επίπεδα της ATP ελαττώνονται in vivo και σε καλλιέργεια ηπατοκυττάρων μετά από χορήγηση τοξικής δόσης παρακεταμόλης [838][839][840] . Παρόμοιες μεταβολές διαπιστώνονται με την προσθήκη NAPQI στα ηπατοκύτταρα 841 .…”

Section: μιτοχόνδρια και ηπατοτοξικότητα παρακεταμόληςunclassified

Η Επίπτωση Της Δράσης Των PAF-αναστολέων Στον Κυτταρικό Κύκλο Μετά Από Παρακεταμόλη Επαγόμενη Ηπατική Βλάβη Σε Επίμυς

Λεκάκος¹

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Στην παρούσα διδακτορική διατριβή μελετάται η επίδραση ενός αναστολέα του παράγοντα ενεργοποίησης αιμοπεταλίων (PAF) στον κυτταρικό κύκλο ηπατοκυττάρων σε πειραματικό μοντέλο της ηπατοτοξικότητας από παρακεταμόλη σε επίμυς. Η παρακεταμόλη αποτελεί ένα από τα πιο κοινά χορηγούμενα φάρμακα και ταυτόχρονα μια από τις πιο συχνές αιτίες οξείας ηπατικής ανεπάρκειας. Από την άλλη, ο κυτταρικός κύκλος διαδραματίζει πρωταρχικό ρόλο τόσο σε φυσιολογικές λειτουργίες του οργανισμού, όπως η ομοιόσταση, η επούλωση και η αναγέννηση των ιστών, όσο και σε παθολογικές καταστάσεις, όπως η ανάπτυξη κακοήθειας. Εξίσου επίκαιρο και σημαντικό θέμα με προεκτάσεις στην κλινική πράξη αποτελεί και η ενίσχυση της ηπατικής αναγέννησης, που δύναται να αντισταθμίσει τη μακρά λίστα αναμονής για μεταμόσχευση και την έλλειψη μοσχευμάτων για τους ασθενείς με ηπατική ανεπάρκεια τελικού σταδίου. Η έρευνα αυτή πιστοποίησε την ευεργετική επίδραση του αναστολέα του PAF στην ηπατοτοξικότητα από παρακεταμόλη, η οποία συνίσταται στη μείωση των διαμεσολαβητών της φλεγμονής και των μιτωγόνων παραγόντων και έχει ως αποτέλεσμα μειωμένη ανάγκη για ηπατική αναγέννηση. Ως εκ τούτου, ενθαρρύνεται η χορήγηση του αναστολέα του PAF και σε κλινικές μελέτες. […]

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Acetaminophen toxicity results in site-specific mitochondrial damage in isolated mouse hepatocytes.

Cited by 197 publications

References 30 publications

Comparative evaluation of N-acetylcysteine and N-acetylcysteineamide in acetaminophen-induced hepatotoxicity in human hepatoma HepaRG cells

Comparative evaluation of N-acetylcysteine and N-acetylcysteineamide in acetaminophen-induced hepatotoxicity in human hepatoma HepaRG cells

The development and hepatotoxicity of acetaminophen: reviewing over a century of progress

Η Επίπτωση Της Δράσης Των PAF-αναστολέων Στον Κυτταρικό Κύκλο Μετά Από Παρακεταμόλη Επαγόμενη Ηπατική Βλάβη Σε Επίμυς

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