Module 9: Organ-Specific Toxicity - Aflatoxins

Aflatoxins

• Aflatoxins are polycyclic, unsaturated, and coumarin derivatives from yeast (Aspergillus flavus and A. parasiticus)
• Human exposure to aflatoxins occurs through food consumption, particularly through contaminated groundnuts (green) and maize (brown spots)
• Aflatoxin B1 is a co-factor in 60% of liver cancer cases in Sudan, leading to Hepatocellular carcinoma (HCC)
• MOA: Aflatoxin B1 causes p53 mutations, leading to p53 inactivation, proliferation, loss of growth control, and genetic alterations resulting in HCC
• Visible as yellow patches in the liver, causing damage to DNA

Mechanisms of Tox

• Genotox

Degradation Methods

• Extruder
• Ammonia

Snake Venom

Anatomy of Venomous Snakes

• Venom glands release venom through pressure on compressor muscle (in the ‘cheek’) and via venom duct into fangs and into tissue
• Examples: Rattle snakes, black mamba

Toxins in Snake Venom

• Phospholipase A2: local and systemic myotox, pain, damage to lymphatic vessels, oedema, neurotox, nephrotox, and hemolysis
• Snake venom metalloproteinases (SVMP): hemorrhage, myonecrosis, extracellular matrix degradation, blistering, pain, oedema, cardiovascular shock, nephrotox, and coagulopathy
• Hyaluronidases: ECM degradation
• Three finger toxins: cytotox, necrosis, and neurotox
• Dendrotox: neurotox
• Snake venom serine proteinases (SVSP): coagulopathy, oedema, and hypotension
• Vasoactive peptides: hypotension
• Disintegrins: inhibition of platelet aggregation
• C-type lectin like proteins: inhibition or promotion of platelet aggregation and thrombocytopenia
• Cysteine-rich secretory proteins: smooth muscle paralysis
• Natriuretic peptides: hypotension
• Sarafotoxins: cardiotox

Symptoms of Envenomation

• Swelling and blistering
• Gangrene
• Bleeding gums
• Skin necrosis
• Paralysis of eye muscles and upper eyelid

Mechanism of Neurotox

Capturing Snake Venom

• Snake venom milking
• Advantages: qualitative and quantitative information about toxins present, development of antivenom
• Capturing toxins: antivenom immobilization, column with venom Ab, toxins bind, rest goes through, elution, and further characterization
• Toxins are promising for treatment of cerebro and cardiovascular diseases, arteriosclerosis, blood clotting diseases, wound healing, hypertension, cancer, and viral infections

TGN1412

• Medicine supposed for treatment of B-cell lymphatic leukemia and rheumatoid arthritis
• MOA: normal trigger of immune response, Ag binds T-cell R, co-stimulatory molecule (CD28) for the activation of immune cells

MOA for Disease

• Activation of CD4+ T-cells, no longer tolerance to leukemic B-cells, elimination of leukemic B-cells
• Activation of T-reg (also have expression of CD28)
• Activation of other lymphocytes T4

MOA of Tox

• Cytokine storm: very high number of cytokines (first days after infusion), headache, hypotension, tachycardia, fever, lymphopenia, monocytopenia
• Cortico injection (reduction of immune response) = transient improvement
• Multi-organ failure, ↑ ALT (liver damage), necrosis of extremities

This module covers the toxicity of aflatoxins, including their sources, human exposure, and health effects such as hepatocellular carcinoma. Aflatoxins are polycyclic, unsaturated coumarin derivatives from Aspergillus flavus and A. parasiticus.