Taming Food-Drug Interaction Risk: Potential Inhibitory Effects of Citrus Juices on Cytochrome Liver Enzymes Can Safeguard the Liver from Overdose Paracetamol-Induced Hepatotoxicity

Paracetamol overdoseis the leading cause of drug-induced hepatotoxicityworldwide. Because of N-acetyl cysteine'slimited therapeutic efficacy and safety, searching for alternativetherapeutic substitutes is necessary. This study investigated fourcitrus juices: Citrus sinensis L. Osbeck var. Pineapple (pineapple sweet orange), Citrus reticulata Blanco x Citrussinensis L. Osbeck (Murcott mandarin), Citrus paradisi Macfadyen var. RubyRed (red grapefruit), and Fortunella margarita Swingle (oval kumquat) to improve the herbal therapy against paracetamol-inducedliver toxicity. UHPLC-QTOF-MS/MS profiling of the investigated samplesresulted in the identification of about 40 metabolites belonging todifferent phytochemical classes. Phenolic compounds were the mostabundant, with the total content ranked from 609.18 to 1093.26 & mu;ggallic acid equivalent (GAE)/mL juice. The multivariate data analysisrevealed that phloretin 3 & PRIME;,5 & PRIME;-di-C-glucoside, narirutin,naringin, hesperidin, 2-O-rhamnosyl-swertisin, fortunellin(acacetin-7-O-neohesperidoside), sinensetin, nobiletin,and tangeretin represented the crucial discriminatory metabolitesthat segregated the analyzed samples. Nevertheless, the antioxidantactivity of the samples was 1135.91-2913.92 & mu;M Troloxeq/mL juice, 718.95-3749.47 & mu;M Trolox eq/mL juice, and2304.74-4390.32 & mu;M Trolox eq/mL juice, as revealed from2,2 & PRIME;-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid, ferric-reducingantioxidant power, and oxygen radical absorbance capacity, respectively.The in vivo paracetamol-induced hepatotoxicity modelin rats was established and assessed by measuring the levels of hepaticenzymes and antioxidant biomarkers. Interestingly, the concomitantadministration of citrus juices with a toxic dose of paracetamol effectivelyrecovered the liver injury, as confirmed by normal sections of hepatocytes.This action could be due to the interactions between the major identifiedmetabolites (hesperidin, hesperetin, phloretin 3 & PRIME;,5 & PRIME;-di-C-glucoside,fortunellin, poncirin, nobiletin, apigenin-6,8-digalactoside, 6 & PRIME;,7 & PRIME;-dihydroxybergamottin,naringenin, and naringin) and cytochrome P450 isoforms (CYP3A4, CYP2E1,and CYP1A2), as revealed from the molecular docking study. The mostpromising compounds in the three docking processes were hesperidin,fortunellin, poncirin, and naringin. Finally, a desirable food-druginteraction was achieved in our research to overcome paracetamol overdose-inducedhepatotoxicity.