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

Aya S Shalaby; Hanaa H Eid; Riham A El-Shiekh; Osama G Mohamed; Ashootosh Tripathi; Ahmed A Al-Karmalawy; Amany A Sleem; Fatma Adly Morsy; Khaled M Ibrahim; Soad H Tadros; Fadia S Youssef

doi:10.1021/acsomega.3c03100

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

ACS Omega. 2023 Jul 17;8(29):26444-26457. doi: 10.1021/acsomega.3c03100. eCollection 2023 Jul 25.

Authors

Affiliations

¹ Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
² Natural Products Discovery Core, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
³ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt.
⁵ Pharmacology Department, National Research Centre, Dokki, Cairo 12622, Egypt.
⁶ Pathology Department, National Research Centre, Dokki, Cairo 12622, Egypt.
⁷ Department of Pharmacognosy, Faculty of Pharmacy, Ain-Shams University, Abbasia, Cairo 11566, Egypt.

Abstract

Paracetamol overdose is the leading cause of drug-induced hepatotoxicity worldwide. Because of N-acetyl cysteine's limited therapeutic efficacy and safety, searching for alternative therapeutic substitutes is necessary. This study investigated four citrus juices: Citrus sinensis L. Osbeck var. Pineapple (pineapple sweet orange), Citrus reticulata Blanco × Citrus sinensis L. Osbeck (Murcott mandarin), Citrus paradisi Macfadyen var. Ruby Red (red grapefruit), and Fortunella margarita Swingle (oval kumquat) to improve the herbal therapy against paracetamol-induced liver toxicity. UHPLC-QTOF-MS/MS profiling of the investigated samples resulted in the identification of about 40 metabolites belonging to different phytochemical classes. Phenolic compounds were the most abundant, with the total content ranked from 609.18 to 1093.26 μg gallic acid equivalent (GAE)/mL juice. The multivariate data analysis revealed that phloretin 3',5'-di-C-glucoside, narirutin, naringin, hesperidin, 2-O-rhamnosyl-swertisin, fortunellin (acacetin-7-O-neohesperidoside), sinensetin, nobiletin, and tangeretin represented the crucial discriminatory metabolites that segregated the analyzed samples. Nevertheless, the antioxidant activity of the samples was 1135.91-2913.92 μM Trolox eq/mL juice, 718.95-3749.47 μM Trolox eq/mL juice, and 2304.74-4390.32 μM Trolox eq/mL juice, as revealed from 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid, ferric-reducing antioxidant power, and oxygen radical absorbance capacity, respectively. The in vivo paracetamol-induced hepatotoxicity model in rats was established and assessed by measuring the levels of hepatic enzymes and antioxidant biomarkers. Interestingly, the concomitant administration of citrus juices with a toxic dose of paracetamol effectively recovered the liver injury, as confirmed by normal sections of hepatocytes. This action could be due to the interactions between the major identified metabolites (hesperidin, hesperetin, phloretin 3',5'-di-C-glucoside, fortunellin, poncirin, nobiletin, apigenin-6,8-digalactoside, 6',7'-dihydroxybergamottin, naringenin, and naringin) and cytochrome P450 isoforms (CYP3A4, CYP2E1, and CYP1A2), as revealed from the molecular docking study. The most promising compounds in the three docking processes were hesperidin, fortunellin, poncirin, and naringin. Finally, a desirable food-drug interaction was achieved in our research to overcome paracetamol overdose-induced hepatotoxicity.