A Systematic Perspective on the Metabolic Interplay between Gallic Acid and Paracetamol.

Abstract

Abstract: Acetaminophen (Paracetamol; APAP) is a widely utilized over-the-counter analgesic and antipyretic medication. However, elevated doses or chronic exposure lead to acute centrilobular hepatic necrosis via the accumulation of its toxic reactive intermediate, N-acetyl-p-benzoquinone imine (NAPQI). Gallic acid (3,4,5-trihydroxybenzoic acid), a major naturally occurring polyphenol in plants such as Terminalia belerica, green tea, and red wine, exhibits potent antioxidant, anti-inflammatory, antimutagenic, and hepatoprotective activities. This review presents a comprehensive assessment of the individual metabolic pathways of acetaminophen and gallic acid, detailing phase I bioactivation, phase II conjugation (glucuronidation, sulfation, and methylation), and renal elimination. Furthermore, it delineates the combined metabolic interplay and mechanistic pathways through which gallic acid mitigates APAP-induced hepatotoxicity by suppressing Cytochrome P450 (CYP2E1) bioactivation, scavenging reactive oxygen species (ROS), restoring intracellular glutathione (GSH) reserves, stabilizing mitochondrial membranes, and regulating biochemical markers. Keywords: Gallic Acid, Acetaminophen, Hepatotoxicity, NAPQI, Phase II Conjugation, Glutathione, CYP2E1, Oxidative Stress.