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

Abstract

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.

Prevention and reversal of selenite‐induced cataracts by N‐acetylcysteine amide in Wistar rats

“…This has been verified in previous studies, as well as its ability to chelate Cu 2+ , scavenge free-radicals, and protect against oxidative stress [29][30][31][32][33][34][35][36]. Our lab has demonstrated NACA's improved antioxidant ability compared to that of NAC [33,37]. Furthermore, NACA is effective at lower concentrations than NAC, which helps to prevent the various adverse effects that are associated with administration of higher doses of NAC [26,31,[38][39][40].…”

N-Acetylcysteine Amide Exerts Possible Neuroprotective Effects in Newborn Pigs after Perinatal Asphyxia

“…On the other hand, our group showed previously that NAC attenuated the increase of oxidative stress in a neonatal pig model and reduced the levels of IL-1β [7]. Moreover, several investigators have displayed the many similar antioxidative effects of NAC and NACA [8,9]. …”

“…Recently, it has been revealed that NAC amide (NACA), an NAC derivate with higher bioavailability and enhanced antioxidant properties [8,9], may significantly mitigate the detrimental consequences of various toxic substances in different organs, including the lungs and kidneys [10,11,12]. …”

N-acetylcysteineamide protects against manganese-induced toxicity in SHSY5Y cell line

“…However, N-acetylcysteineamide's (NACA) characteristics as a drug were improved over NAC by neutralizing the carboxylic group of NAC, which makes the NACA molecule more lipophilic and, therefore, enhances its ability to penetrate cellular membranes (Grinberg et al, 2005). In addition, our own studies demonstrated that NACA is better than NAC in alleviating oxidative stress (Tobwala et al, 2013(Tobwala et al, , 2014. The enhanced ability to penetrate cells allows NACA to be administered at a lower dose than NAC, giving the drug a greater therapeutic index and lowering the risk of side effects that traditionally have been associated with higher doses of NAC (Cotgreave, 1997).…”