Comparing N-acetylcysteine and 4-methylpyrazole as antidotes for acetaminophen overdose

Abstract

Acetaminophen (APAP) overdose can cause hepatotoxicity and even liver failure. N-acetylcysteine (NAC) is still the only FDA-approved antidote against APAP overdose 40 years after its introduction. The standard oral or intravenous dosing regimen of NAC is highly effective for patients with moderate overdoses who present within 8 h of APAP ingestion. However, for late-presenting patients or after ingestion of very large overdoses, the efficacy of NAC is diminished. Thus, additional antidotes with an extended therapeutic window may be needed for these patients. Fomepizole (4-methylpyrazole), a clinically approved antidote against methanol and ethylene glycol poisoning, recently emerged as a promising candidate. In animal studies, fomepizole effectively prevented APAP-induced liver injury by inhibiting Cyp2E1 when treated early, and by inhibiting c-jun N-terminal kinase (JNK) and oxidant stress when treated after the metabolism phase. In addition, fomepizole treatment, unlike NAC, prevented APAP-induced kidney damage and promoted hepatic regeneration in mice. These mechanisms of protection (inhibition of Cyp2E1 and JNK) and an extended efficacy compared to NAC could be verified in primary human hepatocytes. Furthermore, the formation of oxidative metabolites was eliminated in healthy volunteers using the established treatment protocol for fomepizole in toxic alcohol and ethylene glycol poisoning. These mechanistic findings, together with the excellent safety profile after methanol and ethylene glycol poisoning and after an APAP overdose, suggest that fomepizole may be a promising antidote against APAP overdose that could be useful as adjunct treatment to NAC. Clinical trials to support this hypothesis are warranted.

Keywords: 4-Methylpyrazole; Acetaminophen; Fomepizole; Hepatotoxicity; N-Acetylcysteine; c-Jun N-terminal kinase.

Figure 1:. 4MP protects throughout the continuum of APAP pathophysiology while NAC has restricted benefit to the injury phase.

APAP pathophysiology can be divided into an injury phase (left) where active hepatocyte cell death produces ongoing centrilobular necrosis, and a recovery phase (right), where recovery and regeneration of surviving cells repopulates areas of necrosis. During the injury phase, enhanced production of the reactive metabolite NAPQI from APAP depletes hepatic GSH stores and subsequently forms mitochondrial protein adducts. This results in superoxide release into the cytosol which activates the MAP kinase, JNK, inducing its translocation to mitochondria. This amplifies mitochondrial oxidative and nitrosative stress, resulting in induction of the mitochondrial permeability transition pore (MPTP) opening and release of mitochondrial intermembrane proteins endonuclease G (EndoG) and apoptosis inducing factor (AIF) into the cytosol with their translocation to the nucleus. This then induces DNA fragmentation which ultimately causes hepatocyte necrosis. Since NAC and 4MP target several of these early mechanisms, both are protective during the injury phase, where 4MP inhibits cytochrome P450 to prevent NAPQI formation and also inhibits JNK to prevent amplification of mitochondrial damage, while NAC replenishes hepatic GSH stores and supports mitochondrial bioenergetics. However, during the recovery phase, when mild reactive oxygen species (ROS) production may enable activation of the AMPK and PGC1α mediated pathways of mitochondrial biogenesis in regenerating hepatocytes, 4MP or NAC treatment has differing outcomes in mice. While 4MP treatment seems to enhance these beneficial responses, NAC compromises mitochondrial biogenesis by modulating intracellular ROS and GSH levels to blunt the APAP-induced AMPK response.

Figure 2:. Rumack-Matthew Nomogram.

Nomogram with the original 200-line and the 150-line used in the United States National Multicenter Study (USNMS) protocol [55,57]. Source: Wikimedia Commons