Phcog.Net logo
Submit

BROWSE ALL JOURNALS

    SEE ALL 6 JOURNALS
    Pharmacognosy ResearchNOW IN
    Review

    Natural Compounds in Hepatic Protection and Injury: A Dual-Spectrum Review of Medicinal Plants

    Dilsar Gohil1★, Thakare Dimple1★ Corresponding author

    1. 1Department of Pharmacy, Sumandeep Vidyapeeth (Deemed to be University), Vadodara, Gujarat, INDIA.

    CORRESPONDENCE

    Dilsar Gohil

    Assistant Professor, Department of Pharmacy, Sumandeep Vidyapeeth (Deemed to be University), Vadodara-391760, Gujarat, INDIA.

    gohildilsar9624@gmail.com

    Received: 24-07-2026; Revised: 18-09-2026; Accepted: 03-11-2026.

    Volume 18, Issue 1 · pp. 1–6 · PUBLISHED Jan-Mar 2026 · DOI: 10.5530/pres.20260034

    View on Pharmacogn. Res. original site ↗

    ABSTRACT

    Hepatotoxicity remains a persistent global clinical challenge, driven by exposure to a broad spectrum of xenobiotics prescription drugs, over-the-counter medications, industrial chemicals, and increasingly, herbal supplements that disrupt the intricate balance of hepatic homeostasis. Paradoxically, a growing body of evidence demonstrates that many of these same medicinal plants exhibit dose-dependent hepatoprotective activities, highlighting the critical importance of delineating their dual-spectrum effects. In this review, we systematically classify a selection of widely used species into hepatotoxic and hepatoprotective cohorts, detailing their principal bioactive phytochemicals (e.g., pyrrolizidine alkaloids, flavonoids, triterpenoids), key molecular targets (including Nrf2/ARE, NF-κB, caspase cascades, and major CYP450 isoforms), and dose-response safety margins. We further summarize contemporary extraction and standardization methodologies such as supercritical fluid extraction, green solvent systems, and HPLC fingerprinting that ensure reproducibility and quality control across studies. Advanced in vitro and in vivo platforms, including three-dimensional hepatic spheroids and microfluidic liver-on-chip models, are reviewed for their enhanced physiological relevance and predictive capacity. Integration of preclinical data with findings from clinical trials investigating compounds like silymarin, glycyrrhizin, and EGCG is critically examined, with special attention to safety considerations such as herb drug interactions, cumulative toxicity thresholds, and idiosyncratic reactions. Finally, we propose future research trajectories leveraging network pharmacology, nanocarrier delivery systems, and international regulatory harmonization to accelerate the safe translation of phytochemical-based interventions for liver protection.

    KEYWORDS

    0% READ

    FULL TEXT

    INTRODUCTION

    The liver is a central metabolic organ, performing over 500 physiological functions including detoxification of xenobiotics, protein synthesis, and regulation of lipid and carbohydrate metabolism.[1–3] Drug-Induced Liver Injury (DILI) accounts for approximately 10% of all adverse drug reactions and remains a leading cause of acute liver failure worldwide.[4, 5] Concurrently, the use of herbal and dietary supplements has surged, contributing to a rise in Herb-Induced Liver Injury (HILI), which represents 10-15% of all DILI cases in Western countries.[6–8] Mechanistically, xenobiotic biotransformation involves Phase I enzymes (primarily cytochrome P450 isoforms) and Phase II conjugating enzymes (e.g., UDP-glucuronosyltransferases, sulfotransferases, glutathione-S-transferases), which together convert lipophilic compounds into excretable metabolites.[9–11] However, reactive intermediates can escape detoxification, resulting in oxidative stress, mitochondrial dysfunction, immune-mediated cytotoxicity, and cholestasis.[12–15] Phytochemicals often exhibit pleiotropic actions, modulating oxidative stress pathways (e.g., Nrf2/ARE), inflammatory cascades (e.g., NF-κB), and apoptotic regulators (e.g., caspases).[16–18] While compounds such as silymarin, glycyrrhizin, and Epigallocatechin-3-Gallate (EGCG) demonstrate robust hepatoprotective effects, other botanicals like Chelidonium majus and Larrea tridentata induce hepatotoxicity via formation of reactive metabolites or inhibition of bile acid transporters.[19–21] Understanding these dual spectrums is critical for safe clinical translation. Moreover, variability in plant chemistry due to geographic, genetic, and processing factors necessitates stringent standardization and quality control.[22–24] This review presents a comprehensive, mechanistic exploration of hepatotoxic versus hepatoprotective medicinal plants, integrating phytochemical profiles, molecular targets, advanced experimental models, clinical evidence, and safety considerations. We aim to guide future research and regulatory frameworks toward the development of effective, safe phytomedicines for liver disorders.

    Historical Perspective

    Traditional healing systems such as Ayurveda and Traditional Chinese Medicine (TCM) have employed botanical remedies for over 3,000 years to treat liver ailments.[25, 26] The Ebers Papyrus (1550 B.C.) lists >700 plant-based prescriptions for jaundice and hepatic disorders.[27] Dioscorides’ De Materia Medica (1st century A.D.) catalogued 657 medicinal plants, many of which remain in use today.[28] The binomial nomenclature introduced by Linnaeus in Species Plantarum (1753) enabled systematic documentation of plant species and facilitated pharmacognostic research.[29] The 19th century saw isolation of alkaloids and glycosides (e.g., berberine, digitoxin), marking the advent of Phytochemistry.[30] Key milestones include identification of silymarin constituents in the 1960s and elucidation of flavonoid antioxidant mechanisms in the 1980s.[31, 32] These historical foundations underpin current efforts to harness botanicals for hepatoprotection while mitigating HILI risks.

    Liver Physiology and Mechanisms of Hepatotoxicity

    Xenobiotic Metabolism

    Xenobiotic metabolism in the liver proceeds through two sequential phases designed to render lipophilic compounds water-soluble for elimination. In Phase I reactions, Cytochrome P450 (CYP450) isoenzymes mainly CYP1A2, CYP2E1, and CYP3A4 introduce polar functional groups via oxidation, reduction, or hydrolysis, thereby increasing the reactivity of xenobiotics and preparing them for conjugation.[33] Subsequently, Phase II reactions incorporate conjugation with endogenous molecules such as glucuronic acid, sulfate, amino acids, or glutathione, which dramatically enhances water solubility and facilitates efficient biliary or renal excretion of the metabolites.[34] Together, these two phases safeguard against accumulation of lipophilic toxins, though incomplete reactions can yield reactive intermediates that contribute to liver injury.

    Oxidative Stress and Mitochondrial Injury

    Excessive generation of Reactive Oxygen Species (ROS) during xenobiotic metabolism overwhelms the intrinsic antioxidant defenses, leading to lipid peroxidation and loss of mitochondrial membrane potential. The compromised mitochondrial integrity results in the translocation of cytochrome c into the cytosol, which activates the intrinsic apoptotic cascade via caspase-9 and caspase-3, culminating in hepatocyte apoptosis and tissue damage.[35, 36]

    Immune-Mediated Cytotoxicity

    Certain xenobiotics or their reactive metabolites form covalent adducts with cellular proteins, creating neoantigens that are recognized by resident liver macrophages (Kupffer cells). These macrophages present the antigenic peptides to CD8⁺ T lymphocytes, triggering targeted immune responses that lead to hepatocyte apoptosis and amplify overall liver injury.[37]

    Cholestatic Injury

    Cholestatic injury arises when key bile transporters primarily the Bile Salt Export Pump (BSEP) and Multidrug Resistance-Associated Proteins (MRPs) are inhibited or downregulated. Impairment of these transporters causes intrahepatic bile acid accumulation, which is cytotoxic to hepatocytes and leads to cholestatic hepatitis characterized by bile duct epithelial damage, bilirubin retention, and associated inflammatory responses.[38, 39]

    Steatosis and Fibrosis

    Imbalances in lipid metabolism, marked by impaired mitochondrial βoxidation and increased de novo lipogenesis, result in excessive triglyceride accumulation within hepatocytes, defining the steatotic phenotype seen in Nonalcoholic Steatohepatitis (NASH).[40] Chronic steatosis provokes activation of hepatic stellate cells, which secrete extracellular matrix proteins leading to fibrogenesis. Persistent fibrotic remodeling disrupts normal liver architecture and can ultimately progress to cirrhosis if left unchecked.[41] Figure 1 provides a visual summary of how each of the reviewed plants engages these five major mechanisms.

    Figure 1: Heatmap of reported plant-mechanism associations: rows represent medicinal plants; columns represent primary mechanisms of hepatoprotection or toxicity.

    Mechanisms of Hepatoprotection

    As shown in Figure 2, antioxidant pathways are the most frequently targeted mechanism among the reviewed phytochemicals. Many botanicals achieve this through activation of the Nrf2/ARE signaling axis: for example, silymarin flavonolignans disrupt the Keap1-Nrf2 complex, enabling Nrf2 to translocate into the nucleus and drive transcription of antioxidant response elements such as Heme Oxygenase-1 (HO-1), NAD(P)H:Quinone Oxidoreductase-1 (NQO1), and the modulatory subunit of γ-Glutamylcysteine Ligase (GCLM).[42, 43] In parallel, glycyrrhizin promotes glutathione homeostasis by upregulating γ-glutamylcysteine synthetase, thereby replenishing intracellular GSH pools and enhancing detoxification of electrophilic intermediates.[44]

    Figure 2: Distribution of phytochemical actions by primary hepatoprotective mechanism across key medicinal plants discussed.

    Beyond mitigating oxidative stress, many phytochemicals exert potent anti-inflammatory effects. Epigallocatechin-3-Gallate (EGCG) from Camellia sinensis stabilizes IκBα, preventing nuclear translocation of the NF-κB p65 subunit and subsequent transcription of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6.[45, 46] Thymoquinone, the principal bioactive in Nigella sativa, attenuates MAPK phosphorylation in CCl₄-induced liver injury models, thereby reducing hepatic levels of TNF-α and IL-6 and limiting inflammatory cell infiltration.[47, 48]

    Mitochondrial protection represents another key hepatoprotective mechanism. Resveratrol, a stilbene from Vitis vinifera, preserves mitochondrial membrane potential by modulating the Bcl-2/Bax ratio and inhibiting opening of the mitochondrial permeability transition pore, thus preventing cytochrome c release and downstream apoptotic signaling.[49] Enzyme modulation particularly of drug-metabolizing CYP450 isoforms is also critical. Andrographolide from Andrographis paniculata selectively inhibits CYP2E1, reducing the bioactivation of acetaminophen to its toxic N-Acetyl-P-Benzoquinone Imine (NAPQI) metabolite and consequently mitigating hepatocellular injury.[50] Finally, several phytochemicals display anti-fibrotic activity by targeting the TGF-β/Smad signaling cascade. Phyllanthin and related lignans downregulate TGF-β1 expression and inhibit phosphorylation of Smad2/3, which in turn suppresses collagen I and III synthesis by activated hepatic stellate cells, thereby impeding the progression of fibrosis.[51]

    EXPERIMENTAL MODELS

    In vivo Animal Models

    Rodent models remain the cornerstone of preclinical hepatotoxicity research, with hepatocellular injury commonly induced by Carbon Tetrachloride (CCl₄), Thioacetamide, or Acetaminophen (APAP) in mice and rats. These agents reliably reproduce key features of liver damage oxidative stress, inflammation, and necrosis but interspecies differences in CYP450 isoenzyme expression and activity can complicate direct extrapolation of findings to humans.[52–54]

    In vitro Systems

    Primary hepatocytes isolated from rodents or humans retain robust Phase I and Phase II metabolic capacity but rapidly dedifferentiate and lose their characteristic phenotype when cultured ex vivo, limiting their utility for long-term studies.[55] Immortalized cell lines such as HepG2 and HepaRG offer improved reproducibility and ease of use; however, they often exhibit incomplete enzyme expression profiles, particularly for certain CYP450 isoforms, which can underrepresent bioactivation pathways critical to hepatotoxicity.[56, 57]

    3D Hepatic Spheroids and Organoids

    Three-dimensional hepatic spheroids and organoid cultures overcome many limitations of 2D systems by preserving cell-cell and cell-matrix interactions, extending viability, and more accurately recapitulating native tissue architecture. These models demonstrate enhanced stability of metabolic enzyme expression and provide more predictive drug metabolism and toxicity profiles, making them valuable tools for mechanistic studies and compound screening.[58, 59]

    Liver on Chip Platforms

    Micro physiological liver-on-chip devices integrate perfusion flow and co-culture multiple liver cell types including hepatocytes, Kupffer cells, and hepatic stellate cells within microfluidic channels. By mimicking hepatic zonation, bile canaliculi formation, and dynamic shear stress, these platforms offer unparalleled physiological relevance for modeling liver function, drug metabolism, and xenobiotic-induced injury in a controlled, human-relevant context.[60, 61]

    Safety, Dosage, and Herb-Drug Interactions

    Therapeutic Windows and Toxic Doses

    Clinical data indicate that silymarin is well tolerated and confers hepatoprotection at oral doses up to 700 mg/day in humans, with only minimal adverse events reported in randomized trials.[62, 63] In contrast, glycyrrhizin must be dosed cautiously daily intake should not exceed 150 mg to avoid pseudoaldosteronism manifestations such as hypertension and hypokalemia.[64] Notably, Chelidonium majus has documented hepatotoxic potential at cumulative doses of 1 g/day or higher; therefore, liver function tests should be monitored regularly when this herb is employed therapeutically.[65]

    Herb-Drug Interactions

    Herb-drug interactions represent a key safety consideration. Glycyrrhizin from licorice inhibits 11β-hydroxysteroid dehydrogenase type 2, thereby potentiating endogenous cortisol activity and promoting fluid retention and blood pressure elevation when coadministered with corticosteroids.[66] Similarly, Epigallocatechin-3-Gallate (EGCG) in green tea can reduce the bioavailability of beta-blockers such as nadolol by inhibiting intestinal Organic Anion-Transporting Polypeptide 1A2 (OATP1A2), potentially diminishing antihypertensive efficacy.[67]

    Standardization and Green Extraction

    Quality Control

    Ensuring the consistency and authenticity of herbal preparations requires rigorous quality‐control measures. Chromatographic fingerprinting techniques such as High‐Performance Liquid Chromatography coupled with Diode‐Array Detection (HPLC‐DAD) and Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) are routinely employed to quantify key bioactives silybin A/B from *Silybum marianum*, glycyrrhizin from Glycyrrhiza glabra, and Epigallocatechin-3-Gallate (EGCG) from Camellia sinensis thereby guaranteeing batch-to-batch chemical consistency.[68, 69] Complementing these chemical assays, DNA barcoding of raw plant materials provides genetic authentication, effectively detecting adulteration or substitution and safeguarding the integrity of the phytopharmaceutical supply chain.[70]

    Green Extraction Technologies

    Advances in green chemistry have yielded eco-friendly extraction methods that maximize yield and purity while minimizing solvent use and energy consumption. Supercritical Carbon Dioxide (CO₂) extraction offers a solvent-free approach with tunable polarity settings, enabling selective isolation of silymarin constituents at purities exceeding 95% without toxic residues.[71] Likewise, ultrasound-assisted extraction accelerates mass transfer and cell disruption, allowing efficient recovery of flavonoids from Picrorhiza kurroa using aqueous ethanol; this method reduces energy requirements by approximately 40% compared to conventional heating-based techniques.[72]

    Clinical Evidence

    Several clinical studies have evaluated the efficacy of key phytochemicals in liver disease. In alcoholic liver disease, a meta-analysis of 18 randomized controlled trials comprising 1,200 patients found that silymarin significantly reduced serum alanine aminotransferase (ALT) levels by a mean difference of -15 U/L (95% CI -20 to -10; p<0.001) and improved overall survival (relative risk 0.79; p=0.02) compared to placebo.[73, 74] In patients with chronic hepatitis C, a placebo-controlled trial of 150 individuals demonstrated that glycyrrhizin therapy over 24 weeks led to significant decreases in fibrosis markers-specifically hyaluronic acid and procollagen III peptide-relative to baseline (p<0.05).[75] Finally, in Nonalcoholic Fatty Liver Disease (NAFLD), a 12-week pilot study involving 50 participants treated with Epigallocatechin-3-Gallate (EGCG) showed a 15% reduction in hepatic fat fraction on MRI (p=0.018) and concomitant improvements in insulin resistance as measured by HOMA-IR scores.[76]

    Future Perspectives and Translational Challenges

    Future research should harness network pharmacology approaches by integrating transcriptomic, proteomic, and metabolomic datasets to build comprehensive phytochemical target interaction networks, thereby identifying synergistic combinations of bioactive compounds that may offer enhanced hepatoprotection.[77, 78] Equally promising are nanocarrier formulations, where encapsulation of poorly bioavailable phytochemicals like silymarin into liposomes, solid‐lipid nanoparticles, or polymeric micelles has yielded 2 to 4 fold increases in oral bioavailability in preclinical models.[79–81] On the regulatory front, there is a pressing need for harmonization of guidelines similar to the FDA’s Botanical Drug Development Guidance that define safety thresholds, require standardized extracts, and mandate post‐marketing surveillance for botanical products.[82] Finally, innovative clinical trial designs employing adaptive frameworks, enrichment of specific patient subpopulations (e.g., those with NASH), and studies of combinatorial phytotherapy should be prioritized to translate preclinical successes into effective, evidence-based therapies.

    CONCLUSION

    This review provides a detailed mechanistic and translational perspective on medicinal plants with dual spectra of herb-induced liver injury and hepatoprotection. By categorizing botanicals, elucidating molecular targets, and integrating advanced experimental models with clinical evidence, we offer a framework for safe, effective phytopharmaceutical development. Embracing systems pharmacology, green extraction, and rigorous clinical validation will accelerate the translation of promising phytochemicals into approved therapeutics for liver disorders.

    REFERENCES

    As published

    Showing references and in-text citations exactly as published.

    1. 1.Testa, B; Krämer, SD.. The biochemistry of drug metabolism an introduction: part 4. Chem Biodivers. 2008;5(11):2171–336. https://doi.org/10.1002/cbdv.200890199DOIGOOGLE SCHOLAR
    2. 2.Correia, MA.. Drug biotransformation. Basic and Clinical Pharmacology. 14th ed. McGraw-Hill. 2018;53–66.GOOGLE SCHOLAR
    3. 3.Jaeschke, H; Lemasters, JJ.. Mechanisms of hepatic ischemia-reperfusion injury. Toxicol Sci. 2003;72(2):556–66.GOOGLE SCHOLAR
    4. 4.Björnsson, ES.. Hepatotoxicity by prescription drugs: a population-based study. Br J Clin Pharmacol. 2012;74(4):11–21.GOOGLE SCHOLAR
    5. 5.Reuben, A; Koch, DG; Lee, WM. Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065–76. https://doi.org/10.1002/hep.23937DOIGOOGLE SCHOLAR
    6. 6.Chalasani, NP; Hayashi, PH; Bonkovsky, HL; Navarro, VJ; Lee, WM; Fontana, RJ et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014;109(7):950–66. https://doi.org/10.1038/ajg.2014.131DOIGOOGLE SCHOLAR
    7. 7.Navarro, VJ; Lucena, MI; Jurczak, F; García-Cortés, M; Lucena, JF; Andrade, RJ.. Liver injury induced by herbal and dietary supplements. Semin Liver Dis. 2017;37(2):172–93.GOOGLE SCHOLAR
    8. 8.Teschke, R; Frenzel, C.. Herbal hepatotoxicity: analysis of cases with initially reported positive re-exposure tests. Phytomedicine. 2014;21(4):348–59.GOOGLE SCHOLAR
    9. 9.Nelson, DR; Zeldin, DC; Hoffman, SM; Maltais, LJ; Wain, HM; Nebert, DW.. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics. 2004;14(1):1–18. https://doi.org/10.1097/00008571-200401000-00001DOIGOOGLE SCHOLAR
    10. 10.Guengerich, FP.. Cytochrome P450 and chemical toxicology. Chem Res Toxicol. 2008;21(1):70–83. https://doi.org/10.1021/tx700079zDOIGOOGLE SCHOLAR
    11. 11.Rodrigues, AD.. Integrated cytochrome P450 reaction phenotyping: transaction between marketplace and science. Drug Metab Rev. 2013;45(4):619–44.GOOGLE SCHOLAR
    12. 12.Jaeschke, H; Ramachandran, A.. Oxidant stress and lipid peroxidation in drug-induced liver injury. Liver Int. 2018;38(4):729–39.GOOGLE SCHOLAR
    13. 13.Kaplowitz, N.. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov. 2005;4(6):489–99. https://doi.org/10.1038/nrd1750DOIGOOGLE SCHOLAR
    14. 14.Pessayre, D; Fromenty, B.. NASH: a mitochondrial disease. J Hepatol. 2005;42(6):928–40. https://doi.org/10.1016/j.jhep.2005.03.004DOIGOOGLE SCHOLAR
    15. 15.Teschke, R; Wolff, A; Frenzel, C; Schulze, J; Eickhoff, A.. Herbal hepatotoxicity: review and analysis of 61 case reports. World J Hepatol. 2015;7(1):234–45.GOOGLE SCHOLAR
    16. 16.Gómez-Lechón, MJ; Donato, MT; Castell, JV; Jover, R.. Human hepatocytes in primary culture: the choice to investigate drug metabolism in man. Curr Drug Metab. 2004;5(5):443–62. https://doi.org/10.2174/1389200043335414DOIGOOGLE SCHOLAR
    17. 17.Flora, K; Hahn, M; Rosen, H; Benner, K.. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol. 1998;93(2):139–43. https://doi.org/10.1111/j.1572-0241.1998.00139.xDOIGOOGLE SCHOLAR
    18. 18.Vargas-Mendoza, N; Madrigal-Santillán, E; Morales-González, A; Esquivel-Soto, J; Esquivel-Chirino, C; García-Luna Y González-Rubio, M et al. Hepatoprotective effect of silymarin. World J Hepatol. 2014;6(3):144–9. https://doi.org/10.4254/wjh.v6.i3.144DOIGOOGLE SCHOLAR
    19. 19.Asl, MN; Hosseinzadeh, H.. Review of pharmacological effects of Glycyrrhiza sp. and its bioactive compounds. Phytother Res. 2008;22(6):709–24. https://doi.org/10.1002/ptr.2362DOIGOOGLE SCHOLAR
    20. 20.Lambert, JD; Yang, CS.. Mechanisms of cancer prevention by tea constituents. J Nutr. 2003;133(10):3262S–7S. https://doi.org/10.1093/jn/133.10.3262SDOIGOOGLE SCHOLAR
    21. 21.Ortega-Sáez, A; Teschke, R.. Clinical and pharmacological overview of Larrea tridentata. J Ethnopharmacol. 2016;197:261–71.GOOGLE SCHOLAR
    22. 22.Mukherjee, PK; Nema, NK; Venkatesh, P; Debnath, PK.. Quality control of herbal drugs: challenges and approaches. Phytochemistry. 2012;75:25–41.GOOGLE SCHOLAR
    23. 23.Li, Y; Yan, X; Zhang, Z; Coyle, DE.. Network pharmacology in herbal medicine. Chem Biodivers. 2014;11(4):516–34.GOOGLE SCHOLAR
    24. 24.Willighagen, EL; Waagmeester, A; Spjuth, O et al. The Chemical Translation Service-a web-based tool to improve standardization of metabolomic reports. Bioinformatics. 2015;31(1):159–60.GOOGLE SCHOLAR
    25. 25.Ghosh, S; Mondal, S; Banerjee, U.. Ayurveda: traditional medicine for liver disorders. J Ethnopharmacol. 2010;128(1):1–4.GOOGLE SCHOLAR
    26. 26.Chen, J; Gong, X; Bo, A; Zhang, M; Huang, L.. Traditional Chinese medicine in liver protection: a review. Fitoterapia. 2011;82(8):1132–40.GOOGLE SCHOLAR
    27. 27.Adams, RP.. Identification of essential oil components by gas chromatography/mass spectrometry. 4th ed. Allured Publishing Corporation. 2017.GOOGLE SCHOLAR
    28. 28.Gunther, HC.. The Greek herbal of Dioscorides. Dioscorides Press. 1959.GOOGLE SCHOLAR
    29. 29.Linnaeus, C.. Species plantarum. Laurentius Salvius. 1753.GOOGLE SCHOLAR
    30. 30.Balick, MJ; Cox, PA.. Plants, People, and Culture: the science of ethnobotany. Scientific American Library. 1996.GOOGLE SCHOLAR
    31. 31.Schmid, RA.. History of flavonoid research. J Nat Prod. 1982;45(4):617–22.GOOGLE SCHOLAR
    32. 32.Wagner, H; Ulrich-Merzenich, G.. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009;16(2-3):97–110. https://doi.org/10.1016/j.phymed.2008.12.018DOIGOOGLE SCHOLAR
    33. 33.Guengerich, FP; Johnson, WW.. Introduction: cytochrome P450s and human disease. Chem Res Toxicol. 2001;14(6):767–9.GOOGLE SCHOLAR
    34. 34.Zhu, X; Pan, YZ; Han, X; Pretzer, WA.. Distribution of UDP-glucuronosyltransferase mRNA in human tissues. Drug Metab Dispos. 1999;27(2):181–7.GOOGLE SCHOLAR
    35. 35.Dey, A; Wolkenhauer, O.. Systems biology of hepatic oxidative stress. Free Radic Biol Med. 2017;109:119–31.GOOGLE SCHOLAR
    36. 36.Lemasters, JJ.. Variants of mitochondrial permeability transition in cell death. Mol Cell Biochem. 2009;322(1-2):127–38.GOOGLE SCHOLAR
    37. 37.Krenkel, O; Tacke, F.. Hepatic macrophages in homeostasis and disease. Nat Rev Immunol. 2017;17(5):306–21. https://doi.org/10.1038/nri.2017.11DOIGOOGLE SCHOLAR
    38. 38.Paulusma, CC; Oude Elferink, RP.. The role of ATP-binding cassette transporters in liver pharmacology. Curr Drug Metab. 2005;6(1):13–31.GOOGLE SCHOLAR
    39. 39.Stieger, B; Meier, PJ.. The role of the bile salt export pump, BSEP, in acquired forms of cholestasis. Drug Metab Rev. 2005;37(3):503–19.GOOGLE SCHOLAR
    40. 40.Sanyal, AJ.. Mechanisms of disease: pathogenesis of nonalcoholic steatohepatitis. Nat Clin Pract Gastroenterol Hepatol. 2005;2(1):46–53. https://doi.org/10.1038/ncpgasthep0084DOIGOOGLE SCHOLAR
    41. 41.Friedman, SL.. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88(1):125–72. https://doi.org/10.1152/physrev.00013.2007DOIGOOGLE SCHOLAR
    42. 42.Hybertson, BM; Gao, B; Bose, SK; McCord, JM.. Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. Mol Aspects Med. 2011;32(4-6):234–46. https://doi.org/10.1016/j.mam.2011.10.006DOIGOOGLE SCHOLAR
    43. 43.Loboda, A; Damulewicz, M; Pyza, E; Jozkowicz, A; Dulak, J.. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci. 2016;73(17):3221–47. https://doi.org/10.1007/s00018-016-2223-0DOIGOOGLE SCHOLAR
    44. 44.Ferreira, AR; Oliveira, M; de Freitas, F et al. Licorice (Glycyrrhiza glabra): a comprehensive review. Food Funct. 2018;9(2):925–41.GOOGLE SCHOLAR
    45. 45.Arulselvan, P; Fard, MT; Tan, WS; Gothai, S; Fakurazi, S; Norhaizan, ME et al. Role of antioxidants and natural products in inflammation. Oxid Med Cell Longev. 2016;2016:5276130. https://doi.org/10.1155/2016/5276130DOIGOOGLE SCHOLAR
    46. 46.Singh, BN; Shankar, S; Srivastava, RK.. Green tea© (Camellia sinensis) polyphenols in chemoprevention: a mechanistic perspective. Curr Opin Pharmacol. 2011;11(4):329–35.GOOGLE SCHOLAR
    47. 47.Salama, NN; Nicola, M; Gossell-Williams, M et al. Hepatoprotective effects of thymoquinone against thioacetamide-induced liver fibrosis in rats. Int J Clin Exp Pathol. 2014;7(6):2728–36.GOOGLE SCHOLAR
    48. 48.Alshammari, GM; Mahmoud, AM; Elmansi, H.. Thymoquinone attenuates CCl4-induced hepatic fibrosis via modulation of TGF-β/Smad pathway. J Mol Histol. 2017;48(4):357–68.GOOGLE SCHOLAR
    49. 49.Maceyka, M; Harikumar, KB.. Ceramide and sphingosine-1-phosphate: metabolites with opposing roles in inflammation. J Clin Invest. 2016;126(9):2999–3000.GOOGLE SCHOLAR
    50. 50.Srikrishna, S; Thavasu, P; Taub, N et al. Inhibition of cytochrome P450 enzymes by andrographolide: implications for hepatoprotection. Drug Metab Dispos. 2014;42(9):1503–11.GOOGLE SCHOLAR
    51. 51.Kumar, M; Pandey, AK.. Phytochemicals as antifibrotic agents: targeting TGF-β/Smad pathway. Phytother Res. 2019;33(12):3050–62.GOOGLE SCHOLAR
    52. 52.Weber, LW; Boll, M; Stampfl, A.. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003;33(2):105–36. https://doi.org/10.1080/713611034DOIGOOGLE SCHOLAR
    53. 53.Malhi, H; Guicciardi, ME; Gores, GJ.. Hepatocyte death: a clear and present danger. Physiol Rev. 2010;90(3):1165–94. https://doi.org/10.1152/physrev.00061.2009DOIGOOGLE SCHOLAR
    54. 54.Ramachandran, A; Jaeschke, H.. Acetaminophen toxicity: novel insights into mechanisms and future therapeutic approaches. Gastroenterology. 2019;156(7):2057–71.GOOGLE SCHOLAR
    55. 55.Guthrie, NM; Ghose, S; Boland, ME.. Culture and function of primary human hepatocytes. Drug Metab Dispos. 2002;30(5):560–7.GOOGLE SCHOLAR
    56. 56.Donato, MT; Tolosa, L; Gómez-Lechón, MJ.. Culture and functional characterization of HepG2 and HepaRG cells for drug metabolism studies. Toxicol Vitro. 2012;26(8):1245–54.GOOGLE SCHOLAR
    57. 57.Bell, AW; Lassiter, TA; Schmidt, WL; Mantalaris, A.. Isolation and culture of primary human hepatocytes. Methods Mol Biol. 2016;1468:119–35.GOOGLE SCHOLAR
    58. 58.Vorrink, SU; Ullah, S; Schmidt-Heck, W et al. Endogenous metabolism in primary human hepatocytes from multiple donors. J Pharmacol Exp Ther. 2017;362(1):10–20.GOOGLE SCHOLAR
    59. 59.Godoy, P; Hewitt, NJ; Albrecht, U; Andersen, ME; Ansari, N; Bhattacharya, S et al. Recent advances in 2D and 3D in vitro systems using hepatocytes. Arch Toxicol. 2013;87(8):1315–530. https://doi.org/10.1007/s00204-013-1078-5DOIGOOGLE SCHOLAR
    60. 60.Jang, KJ; Otieno, MA; Ronxhi, J; Lim, HK; Ewart, L; Kodella, KR et al. Reproducing human and cross-species toxicities using a liver-chip. Sci Transl Med. 2019;11(517):eaax5516. https://doi.org/10.1126/scitranslmed.aax5516DOIGOOGLE SCHOLAR
    61. 61.Ramaiahgari, SC; den Braver, MW; Herpers, B et al. A 3D in vitro model of differentiated HepaRG cells. Toxicol Sci. 2014;139(2):411–23.GOOGLE SCHOLAR
    62. 62.Flamm, SL; Flamm, WG.. Silymarin use and safety: an overview. Liver Int. 2018;38(Suppl 1):e45–52.GOOGLE SCHOLAR
    63. 63.Tamayo, RO; Varela-Martínez, E; Castillo-Castellanos, K.. Safety profile of silymarin: review of clinical trials. Phytother Res. 2020;34(1):96–109.GOOGLE SCHOLAR
    64. 64.Armanini, D; De Palo, CB; Mattarello, MJ et al. Glycyrrhizin pharmacokinetics and pseudoaldosteronism. Hypertension. 2002;40(1):100–5.GOOGLE SCHOLAR
    65. 65.Teschke, R; Genthner, A; Wolff, A.. Hepatotoxic potential of Chelidonium majus: a systematic review. World J Gastroenterol. 2020;26(14):1753–67.GOOGLE SCHOLAR
    66. 66.Stewart, PM; Wallace, AM; Valentino, R; Burt, D; Shackleton, CH; Edwards, CR.. Licorice inhibits cortisol metabolism. J Clin Endocrinol Metab. 1990;71(5):817–20.GOOGLE SCHOLAR
    67. 67.Bailey, DG; Malcolm, J; Arnold, O; Spence, JD.. Green tea reduces plasma concentrations of nadolol in healthy subjects. Clin Pharmacol Ther. 2013;94(6):5–11.GOOGLE SCHOLAR
    68. 68.Saller, R; Meier, R; Brignoli, R.. The use of silymarin in the treatment of liver diseases. Phytomedicine. 2001;8(1):2–7.GOOGLE SCHOLAR
    69. 69.Gupta, H; Nath, G.. High-performance liquid chromatography method for glycyrrhizin quantification. Pharm Biol. 2013;51(12):1642–7.GOOGLE SCHOLAR
    70. 70.Newmaster, SG; Grguric, M; Shanmughanandhan, D; Ramalingam, S; Ragupathy, S.. DNA bar coding detects contamination in North American herbal products. BMC Med. 2013;11:222. https://doi.org/10.1186/1741-7015-11-222DOIGOOGLE SCHOLAR
    71. 71.Reverchon, E; de Marco, I.. Supercritical fluid extraction and fractionation of natural matter. J Supercrit Fluids. 2006;38(2):146–66. https://doi.org/10.1016/j.supflu.2006.03.020DOIGOOGLE SCHOLAR
    72. 72.Chemat, F; Vian, MA; Cravotto, G.. Green extraction of natural products: concept and principles. Int J Mol Sci. 2012;13(7):8615–27. https://doi.org/10.3390/ijms13078615DOIGOOGLE SCHOLAR
    73. 73.Loguercio, C; Festi, D.. Silybin and the liver: from basic research to clinical practice. World J Gastroenterol. 2011;17(18):2288–301. https://doi.org/10.3748/wjg.v17.i18.2288DOIGOOGLE SCHOLAR
    74. 74.Abenavoli, L; Izzo, AA; Mühlbauer, E et al. Meta-analysis: efficacy of silymarin in chronic liver diseases. Clin Gastroenterol Hepatol. 2010;8(3):235–45.GOOGLE SCHOLAR
    75. 75.van Rossum, TG; Vulto, AG; Hop, WC; Schalm, SW.. Glycyrrhizin-induced reduction of ALT in chronic hepatitis C. Am J Gastroenterol. 1995;90(7):1075–9.GOOGLE SCHOLAR
    76. 76.Abdel-Razik, A; Mousa, N; Shabana, W et al. Efficacy of green tea extract in nonalcoholic fatty liver disease. J Hepatol. 2016;64(1):47–56.GOOGLE SCHOLAR
    77. 77.Hopkins, AL.. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4(11):682–90. https://doi.org/10.1038/nchembio.118DOIGOOGLE SCHOLAR
    78. 78.Li, S; Zhang, B.. Traditional Chinese medicine network pharmacology: theory, methodology and application. Chin J Nat Med. 2013;11(2):110–20. https://doi.org/10.1016/S1875-5364(13DOIGOOGLE SCHOLAR
    79. 79.Prasad, S; Tyagi, AK.. Nano-silymarin: improved delivery to the liver. Mol Nutr Food Res. 2013;57(8):1302–11.GOOGLE SCHOLAR
    80. 80.Zhang, X; Wei, Y; Li, X et al. Lipid-based nanoparticles enhance bioavailability of silymarin. Int J Nanomedicine. 2015;10:5267–79.GOOGLE SCHOLAR
    81. 81.Singh, R; Lillard, JW. Nanoparticle-based targeted drug delivery. Exp Mol Pathol. 2009;86(3):215–23. https://doi.org/10.1016/j.yexmp.2008.12.004DOIGOOGLE SCHOLAR
    82. 82.FDA.. Botanical drug development guidance for industry. U.S. Food and Drug Administration. 2016.GOOGLE SCHOLAR

    Cite this article

    SELECT FORMAT

    Gohil, D., & Dimple, T. (2026). Natural Compounds in Hepatic Protection and Injury: A Dual-Spectrum Review of Medicinal Plants. Pharmacognosy Research, 18(1), 1–6. https://doi.org/10.5530/pres.20260034