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Herbert Desel

Toxicology Target Organs and Mechanism of Action Master Program me Molecular Medicine Universität Göttingen Module ‚Special Aspects of Molecular Medicine‘ Sub-Module ‚Pharmacology‘ 29. Januar 2008. Herbert Desel. Toxicology. deals with INTOXICATIONS (poisonings):

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Herbert Desel

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  1. ToxicologyTarget Organs and Mechanism of ActionMaster Programme Molecular Medicine Universität GöttingenModule ‚Special Aspects of Molecular Medicine‘ Sub-Module ‚Pharmacology‘29.Januar2008 Herbert Desel

  2. Toxicology deals with INTOXICATIONS (poisonings): • Adverse effect(s) of a chemical compound on the body: toxic effect • in most cases taken up from the environment (exposure to xenobiotic) • The illness caused by a toxic effect

  3. Molecular Targets for Toxic Effects • proteins • DNA • lipids • small molecules

  4. Chemical Basis of Toxic Effects • coordinative binding (electrostatic interaction) • covalent binding • directly • activated by metabolism • important role of toxicokinetics

  5. Time Scale • Acute effects • Direct cause: e.g. receptor bindung • Chronic toxic effects • Accumulation of subclinical damage or accumulation of chemical agent

  6. Target Organs of Toxic Effects • nervous system • liver • kidney • ... • many toxic agents cause multi organ damage

  7. Substance Group Example:Organic Solvents • hydrocarbons • alcohols • carbonic acids • small chlorinated hydrocarbons • esters (lactons), ethers, ketones, aldehyds

  8. Example: Organic Solvents • commoneffects • effects caused by onesolvent only

  9. Organic Solvents Common Effects Skin / mucosa: • extraction of fat (loss of protection) • solvent effect • irritation, inflammation • via cytokines, white blood cells • corrosion • necrosis

  10. Corrosion caused by formic acid mixed with dichloro-methane

  11. Organic SolventsCommon Effects Skin / mucosa: • ... Central nervous system • Reduced capacity (reaction time, ataxia), drowsiness, coma • nonspecific interaction with neuronal membrans • Euphoria: excitation • inibiting neurons are more effected in beginning • specific effects in ‚mesolimbic reward system‘ • Risk of substance dependency • tolerance, withdrawal symptoms

  12. Most Important: Ethanol • Long tradition in use in many cultures • recreational stimulant • Social importance • 150 fatalities from acute intoxications • 30,000 fatalities from chronic consumption per year in Germany • 2,500,000 people with alcohol dependency • Ethanol consumption plays a role in > 50 % of all legal procedures / cases

  13. Organic Solvent With High Neurotoxic Potency: Gamma Hydroxybutyric Acid Users‘ term: liquid ecstasy

  14. GHB Case Report (GIZ-Nord Poisons Centre, 1999) • 20yo male to ‚ecstasy and two doses of liquid ecstasy (ostentatious: ‚..a narcotic used for cattle‘) • rapid development of sedation, emergency doctor was called • deep coma, heart rate initially 100 /min, bradycardia developed, insufficient ventilation • quick awakening 2 h later, leaving the hospital against medical advice • GHB found in blood: 123 mg/l

  15. Organic SolventsCommon Effects Skin / mucosa: • ... Central nervous system • ... Peripheral nervous system - • Polyneuropathy (long term exposure) • Malerkrankheit (painters‘ disease, occupational)

  16. Polyneuropathy • Paraesthesia (tingling, numbness, burning, or prickling sensations in the feet or toes, feeling like wearing gloves) • Failure of muscle action (e.g. ataxia) • Axonal swelling (reversible) • Axonal degeneration and demyelination • Failure of nerve signal transmission • Best studied for n-hexane, activated to 2,5-hexanedione,forming pyrrol adducts with primary amino groups leading to cross-linking of neurofilaments

  17. Organic Solvents Skin / mucosa • extraction of fat • Irritation, inflammation • (corrosion) Nervous system - central • Reduced brain capacity, euphoria Nervous system - peripheral • Polyneuropathy (long term exposure) Further organ failures ... caused only by chlorinated hydrocarbons and some ‚toxic‘ alcohols

  18. Tetrachloromethane (CCl4) • Easily absorbed from gastrointestinal tract or skin • CYP based metabolism in the liver forming CCl4- CCl3+ Cl-CCl3 + O2 CCl3OO • induces lipid peroxidation • induces liver failure • leads to jaundice and hepatic coma • rigorously regulated by EU law

  19. Toxic Effects of Alcohols • Ethanol: solvent effects, chronic high dose exposure: several organ damage liver (fatty degeneration, cirrhosis), brain, pancreas ... • Methanol: solvent effects, in addition toxic metabolite effects: acidosis, optical nerve damage • Glycols: solvent effects, in addition toxic metabolite effects: acidosis, renal damage

  20. Hepatotoxic Effect of Ethanol • EtOH is oxidized to acetaldehyde • acetaldehyde inhibits -oxidation of free fatty acids • Alcoholic fatty liver (90 - 100 %) • EtOH induces CYP 2E1 • CYP 2E1 generates reactive oxygen species (ROS) • ROS induce inflammation • Alcohol hepatitis (30 %) • Chronic inflammation induces fibrogenesis • Alcoholic cirrhosis (10 - 20 %) • Lipid peroxidation: trans-hydroxy-2-nonenal • DNA adducts: cancerogenesis • Hepatocellular cancer (1 - 2 %)

  21. Chemical Carcinogenesis 1st step - Initiation: • DNA as target - chemical modification of DNA leads to DNA damage and mutation • Important role of DNA repair • overloaded or impaired 2nd step - Promotion • Stimulation of cell proliferation 3rd step - Progression • Further mutations, invasive growth, metastasis

  22. Ethylene Glycol Automotive Antifreeze

  23. ADH ethylene glycol glycolic aldehyd glycolic acid ADH glycolic acid glyoxylic acid oxalic acid (3%) Ethylene Glycol Metabolism:Metabolic activation to glycolic acid and oxalic acid

  24. Ethylene Glycol Metabolism:Formation of Calcium Oxalate In The Nephron soluble oxalate precipitated calcium oxalate

  25. Toxic Effect of Ethylene Glycol • acute euphoria, drowsiness, coma • metabolic acidosis: blood pH below 7.35 • ventilatory dysfunction (Kussmaul respiration) • multi organ failure • acute renal failure • calcium oxalate precipitates in the nephron • polyuria • anuria

  26. Therapy of Ethylene Glycol Poisoning • Antidote therapy: fomepizol • inhibits formation of toxic metabolite(s) • if treatment starts early • Hemodialysis • enhanced elimination of ethylene glycol and accumulated toxic metabolites

  27. ethylene glycol glycolic aldehyd glycolic acid Fome-pizol ADH glycolic acid glyoxylic acid oxalic acid (3%) Ethylene Glycol • Toxikokinetics • Metabolic activation to glycolic acid and oxalic acid ADH

  28. Methanol • industrial solvent, non-EU parfums • fuel for model aircraft • illegal alcoholic drinks

  29. Love Meter

  30. ADH folic acid Methanol Metabolism Methanol formaldehyde formic acid carbon dioxide

  31. Toxic Effect of Methanol • acute euphoria, drowsiness, coma • metabolic acidosis: blood pH below 7.35 • ventilatory dysfunction (Kussmaul respiration) • multi organ failure • visual disturbances • mechanism unknown (inflammation of optical nerve?) • blindness Therapy: like ethylene glycol poisoning plus folic acid

  32. Overview: Target Organs of Important Toxic Effects • Nervous system: solvents, insecticides • Liver: carbon tetrachloride, paracetamol • Lung: particulate matter, herbicides • Several organs: cyanide, glycols, methanol, benzene, heavy metals, dioxins

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