1 / 32

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):

barclay-jacobson
Download Presentation

Herbert Desel

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related