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Xenobiotics Dr Shamim Akram AIMC


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Xenobiotics Dr Shamim Akram AIMC

  1. 1. INTRODUCTION  Xenobiotics are chemicals not naturally belonging to or originating from a particular organism or an ecosystem.  The term Xenobiotic derived from the GK word “Xenos=Foreigner or Stranger”  The body removes xenobiotics by xenobiotic metabolism. This consists of the deactivation and the excretion of xenobiotics and it happens mostly in the liver.
  2. 2. • Food additives, poisons, toxins, certain drugs, chemicals, environmental pollutants, pesticides and other foreign substances.
  3. 3. Xenobiotics Xenobiotics can be- a) Exogenous - The foreign molecules which are not normally ingested or utilized by the organism but they gain entry through dietary food stuffs, or in the form of certain medicines/ drugs used for a therapeutic cause or are inhaled through environment . Examples- Drugs, food additives, pollutants, insecticides, chemical carcinogens etc.
  4. 4. Xenobiotics can be- b) Endogenous – Though they are not foreign substances but have effects similar to exogenous xenobiotics. These are synthesized in the body or are produced as metabolites of various processes in the body. Examples-Bilirubin, Bile acids, Steroids, Eicosanoids and certain fatty acids.
  5. 5. 6 Source of xenobiotic compounds 1. Petrochemical industry : oil/gas industry, refineries, and the production of basic chemicals e.g. vinyl chloride and benzene 2. Plastic industry : - closely related to the petrochemical industry - uses a number of complex organic compounds such as anti-oxidants, plasticizers, cross-linking agents
  6. 6. 7 3. Pesticide industry : most commonly found central structures are benzene and benzene derivatives, often chlorinated and often heterocyclic 4. Paint industry : major ingredient are solvents, xylene, toluene, methyl ethyl ketone, methyl isobutyl ketone and preservatives 5. Others : Electronic industry, Textile industry, Pulp and Paper industry, Cosmetics and Pharmaceutical industry(Drugs), Wood preservation(Anti-Termite).
  7. 7. Effects of Xenobiotics
  8. 8. Food Chain Effects  Bioaccumulation • Primary producers and lower trophic level organisms take up PCBs(polychlorinated biphenyl), accumulates in the food chain • Higher organisms eating primary producers get more concentrated amounts of toxin  Often people consuming higher organisms are exposed to more toxic forms than factory workers
  9. 9. Human Health • carcinogenous: – Liver cancer – melanoma • immune system – suppressed – swollen thymus gland in infants • reproductive system – reduced birth weight – decrease in gestational ages – Abortions
  10. 10. Human Health Cont. • nervous system – infant neurological functions – short-term memory – Learning • endocrine system – thyroid health • other health effects
  11. 11. Marine and Animal Health • Inhibits plankton growth and photosynthesis affecting the food chain – reduce trophic pathways • Reduce plankton size • Reduce size of higher feeders • Divert carbon flow to non- harvestable species – less plankton = less bigger food fish • Toxic to crustaceans, mollusks, and fish at concentrations of only a few ppb
  12. 12. Phases of Detoxification Processes Phase I Phase II
  13. 13. Oxidation Alcohol Aldehydes Amines Drugs Ethanol → Acetic acid Methanol → Formic acid Benzaldehyde → Benzoic acid Aliphatic amine → Aliphatic acid + Urea
  15. 15. Oxidation Many reactions of cytochrome P450 involve the addition of a hydroxyl group to xenobiotics Hydroxylation
  16. 16. Hydroxylation The responsible enzymes are called monooxygen ases or cytochrome P450
  17. 17. Cytochrome P450
  18. 18. Hydroxylation
  19. 19. Reduction
  20. 20. Hydrolysis
  21. 21. Conjugation Glucuronic acid Glutathione Sulfate Glycine Conjugation means the chemical combination of one compound with another compound.
  22. 22. Conjugation with Glucuronic acid
  23. 23. Conjugation with Glucuronic acid Benzoic acid + → Benzoyl glucuronide + UDP Paracetamol + → Conjugated product + UDP Diclofenac sodium + → Conjugated product + UDP
  24. 24. Conjugation with Glycine
  25. 25. Conjugation with Glutathione
  26. 26. Conjugation with sulfate
  27. 27. Biodegradation of Petroleum compounds Petroleum compounds are categorized into 2 groups • Aliphatic hydrocarbon e.g. alkane, alcohol, aldehyde • Aromatic hydrocarbon e.g. benzene, phenol, toluene, catechol • H.C. (substrate) + O2 H.C.-OH + H2O • H.C. (substrate) + O2 H.C. 32 O H O H monooxygenase dioxygenase
  28. 28. XENOBIOTICS PHASE II CONJUGATION REACTIONS Conjugation Reactions Enzymes Donar Group End Product Toxins Detoxified 1 Glucuronidation UDP- Glucuronide Transferase UDP- Glucuronic Acid Conjugation Product Benzoic Acid Phenol Steroids Morphine 2 Glutathion GSH(reduced) GSSH(oxidized) Glutathion-S- Transferase (Epoxide Hydrolase) Acetyle CoA Mercapturic Acid Drugs: Bromobenzene Diazepam PCM Carcinogens 3 Glycine Acyle CoA-Glycine- Transferase CoA-SH Hippuric Acid Benzoic Acid 4 Glutamine Amino-Transferase Amonia( NH3) Amino gp attach to Glutamic acid to form Glutamine Amonia carried From kidney to liver for detoxification 5 Sulfation Sulfo-Transferase PAPS(Phospho- Adenosyl- Phospho-Sulfate) ‘‘Active Sulfate’’ Alcohcl Phenols 6 Acetylation Acetyle Transferase Acetyle Co A Isoniazid (ATT) 7 Methylation Methyle Transferase S-Adenosyl- Methionine ‘’Active Methionine’’ Histamine Epinephrines
  29. 29. 34
  30. 30. POLYCHLORINATED BIPHENYLS (PCBS) • Synthesized chemicals from petro-chemical industry used as lubricants and insulators in heavy industry • Used because – Low reactivity – Non-flammable – High electrical resistance – Stable when exposed to heat and pressure
  31. 31. Fungal Degradation • Aspergillus niger: fillamentous with cytochrome p450 that attacks lower chlorinated PCB’s • Phanerochaete chrysosporium: White rot fungi can attack even highly chlorinated PCB’s at low conc. (less than 500ppb) while aerobic degradation is occuring at a level of 10ppm.
  32. 32. Some m.o. involved in the biodegradation of xenobiotics Phenolic - Achromobacter, Alcaligenes, compound Acinetobacter, Arthrobacter, Azotobacter, Flavobacterium, Pseudomonas putida - Candida tropicalis Trichosporon cutaneoum - Aspergillus, Penicillium Benzoate & related Arthrobacter, Bacillus spp., compound Micrococcus, P. putida
  33. 33.  Xenobiotics are chemical compounds foreign to the body, such as drugs, food additives, and environmental pollutants  Xenobiotics are metabolized in two phases. The major reaction of phase 1 is hydroxylation catalyzed by a variety of monooxygenases, also known as the cytochrome P450s. In phase 2, the hydroxylated species are conjugated with a variety of hydrophilic compounds such as glucuronic acid, sulfate, or glutathione. The combined operation of these two phases renders lipophilic compounds into water- soluble compounds that can be eliminated from the body.  Xenobiotics can produce a variety of biologic effects, including pharmacologic responses, toxicity, immunologic reactions, and cancer.