Translational Insights into Molecular Mechanisms of Chemical Hepatocarcinogenesis for Improved Human Risk Assessment
Journal Title: Advances in Clinical Toxicology - Year 2024, Vol 9, Issue 1
Abstract
Background: Hepatocellular carcinoma (HCC) is a prevalent liver cancer with major risk factors being hepatitis viral infections, alcohol, non-alcoholic fatty liver disease, and aflatoxin exposure. Both genotoxic and non-genotoxic agents can induce HCC through mechanisms involving DNA damage, oxidative stress, chronic inflammation, and disrupted signaling pathways like MAPK/ERK, PI3K/AKT, WNT/β-catenin and PPARα. While rodent assays are utilized to detect potential chemical hepatocarcinogens, species differences in pathways like PPARα and CAR/PXR activation impact human risk assessment. Purpose: This analysis provides an updated, critical examination of species concordance in mechanisms of hepatic carcinogenesis to inform human safety assessment of rodent liver tumor findings. Main Body: Rodent assays including 2-year bioassays, transgenic models, and short-term studies detect liver tumors through lifetime exposure or early biomarkers. However, rodent-specific PPARα and CAR/PXR activation, along with human risk factors like hepatitis, highlight key interspecies differences. Determining mode of action relevance requires evaluating mechanistic validity and pivotal key events leading to tumors across species. Non-genotoxic compounds eliciting rodent liver tumors can activate PPARα, CAR/PXR, and other pathways triggering increased cell replication; but downstream signaling may differ in human liver. Understanding applicability of these mechanisms in humans as well as incorporating human risk factors into experimental models is critical for accurate risk assessment. Conclusion: In summary, elucidating conserved versus divergent molecular mechanisms of hepatic carcinogenesis between rodents and humans is essential for appropriately interpreting rodent findings and safeguarding human health through science-based risk assessment frameworks and regulatory decision-making processes around potential chemical hazards.
Authors and Affiliations
Addissouky TA , Ali MMA , El Sayed IET , Wang Y and Khalil AA
Keywords
Related Articles
- EP ID EP754423
- DOI 10.23880/act-16000294
- Views 6
- Downloads 0
Antioxidant and Tyrosinase Inhibiting Activities of Ethylacetate, Methanolic and Aqueous Extracts of Basella alba Leaves
Basella alba is a leafy green plant commonly cultivated and consumed as vegetable in many Asian and tropical African communities. The plant has been scientifically proven to possess a number of beneficial effects includ...
Hypersensitivity Reactions and Acute Hepatitis Induced by Therapeutic Doses of Ibuprofen
Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. Diagnosing DRESS is specifically complicated due to the multiplicity of organs involved. The main culprit drugs are...
Waste Management of Seafood Processing Effluents, Hadhramout Governorate, Yemen
Wastewater samples were collected from the Hadhramout Governorate/Yemen. Ten wastewater samples were collected from the biggest three fish canning factories in Hadhramout Governorate/Yemen (Tuna for Canning Packing Fishi...
Exposure of Zebrafish (Danio rerio) to Clioquinol Reveals Embryological and Developmental Toxicity
Clioquinol (CQ) belongs to the 8-hydroxyquinoline family of antimicrobial agents. In the 1970s, CQ was withdrawn from the market due to reported neurotoxicity in humans. Although oral use was discontinued, topical formul...
Mechanism of Action of Nerve Growth Factor Induced Histamine Release from Mast Cells during the Inflammation Process
Mast cells and the biogenic amine, histamine, play a central role in inflammatory reactions. Nerve growth factor (NGF) is essetial for the survival of neurones and has significant role in inflammation and repair of tissu...