A Comparative GC/MS Analysis of Citrus Essential Oils: Unveiling the Potential Benefits of Herb‐Drug Interactions in Preventing Paracetamol‐Induced Hepatotoxicity

Abstract Our study aimed to test the potential of Citrus oils in protecting against paracetamol (PAR)‐induced hepatotoxicity. The essential oils of Pineapple sweet orange (OO), Murcott mandarin (MO), Red grapefruit (GO), and Oval kumquat (KO) were investigated using gas chromatography coupled with mass spectrometry (GC/MS). Twenty‐seven compounds were identified, with monoterpene hydrocarbons being abundant class. d‐Limonene had the highest percentage (92.98 %, 92.82 %, 89.75 %, and 94.46 % in OO, MO, GO, and KO, respectively). Hierarchical cluster analysis (HCA) and principal components analysis (PCA) revealed that octanal, linalool, germacrene D, and d‐limonene were the principal discriminatory metabolites that segregated the samples into three distinct clusters. In vitro antioxidant capacities were ranged from 1.2–12.27, 1.79–5.91, and 235.05–585.28 μM Trolox eq/mg oil for 2,2′‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic (ABTS), ferric‐reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC), respectively. In vivo , citrus oils exhibited a significant reduction in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and nitric oxide (NO). Additionally, there was an increase in glutathione reductase (GSH), and the liver architecture was nearly normal. Molecular docking revealed that d‐limonene exhibited a good inhibitory interaction with cytochrome P450 (CYP450) isoforms 1A2, 3A4, and 2E1, with binding energies of −6.17, −4.51, and −5.61 kcal/mol, respectively.