Xenobiotics aug 2013


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Lecture Presentation, Science and Medical students

Xenobiotics aug 2013

  1. 1. Xenobiotics Dr.  Atif H. Khirelsied Faculty of Medicine International University of Africa Khartoum, Sudan
  2. 2. Introduction to XenobioticsIntroduction to Xenobiotics H d i f i h i l• Humans are exposed to various foreign chemicals e.g.,  drugs, food additives, environmental pollutants • Xenos = strange, foreign • Knowledge of xenobiotic metabolism is essential to  d t di funderstanding of: – Pharmacology and therapeutics D i t ti– Drug interactions – Toxicology
  3. 3. Xenobiotics metabolismXenobiotics metabolism • Occurs mainly in the ER of the liver. • Involves 30 different enzymes.Involves 30 different enzymes. • Occurs in two phases of reactions – Phase I reactions – Phase II reactions • The overall purpose of the two phases is to  increase polarity (water solubility) andincrease polarity (water solubility) and  enhance excretion.
  4. 4. Xenobiotics metabolismXenobiotics metabolism • In some cases it may increase toxicity or  carcinogenicity.g y D ifi i i i i l d• Detoxification is inappropriately used term
  5. 5. Examples of phase I reactionsExamples of phase I reactions • Hydroxylation • DeaminationDeamination • Dehalogenation • Desulfuration • EpioxidationEpioxidation • Peroxygenation • Reduction
  6. 6. Examples of phase II reactionsExamples of phase II reactions • Conjugation with glucuronic acid • Conjugation with glutathioneConjugation with glutathione • Sulfation • Acetylation • MethylationMethylation
  7. 7. Examples of phase I reactions • Hydroxylation B PhenolBenzene Catechol Aniline Parahydroxy aniline
  8. 8. Examples of phase I reactions • OxidationOxidation BenzaldehydeToluene Benzoic acidBenzaldehydeToluene Benzoic acid
  9. 9. Examples of phase I reactions • Oxidation i idMuconic acid Catechol β Ketoadipic acidβ‐Ketoadipic acid + Succinic acidAcetyl‐CoA
  10. 10. Examples of phase I reactions • Oxidation Salicylic acid Gentisic acid Homogentisic acidPhenylacetic acid
  11. 11. Examples of phase I reactions • Concomitant oxidation‐reduction p‐Nitrobenzaldehyde p‐Aminobenzoic acid
  12. 12. Examples of phase I reactions • Deamination A i iArginine
  13. 13. Examples of phase I reactions • Decarboxylation Cadaverine iLysine 
  14. 14. Examples of phase I reactionsExamples of phase I reactions • Hydroxylation • DeaminationDeamination • Dehalogenation • Desulfuration • EpioxidationEpioxidation • Peroxygenation • Reduction
  15. 15. Isoenzymes of cytochrome PIsoenzymes of cytochrome P450 • They are mono‐oxygenases found in the liver  ER. • They catalyze hydroxylation of reactions. • Comprises 11 families of enzymes.p y • Heme containing proteins that give peak  absorbance at 450 nm.
  16. 16. The overall  reaction catalyzed by  CYP450 • RH  +  O2 + NADPH+H → R‐OH + H2O + NADP2 2 • RH represents various substances including:• RH represents various substances including: – Pesticides – Petroleum products – Pollutants, e.g., polychlorinated biphenyls (PCB). – Endogenous substances e.g., steroid hormones,  eicosanoids, fatty acids, retinoids
  17. 17. Cytochrome P NomenclatureCytochrome P450 Nomenclature • CYP  = cytochrome P450 • Arabic number = family (40% homology)Arabic number   family (40% homology) • Letter = subfamily (55% homology) • Arabic number  = Individual enzyme • Example, CYP1A1 
  18. 18. Important features of cytochrome P450 enzymes  h h i1. They are hemoproteins 2. Highly versatile and diverse 3. Widely distributed across species, including  bbacteria. 4. Highly concentrated in the SER of liver cells. 
  19. 19. Important features of cytochrome P450 enzymes  5. A large number of isoforms (about 150)  discovered. 6 C i l f ili (40% i il i )6. Constitute several families (40% similarity)  and subfamilies (55% similarity). 7 Th NADPH t d b t7. They use NADPH to reduce substances.
  20. 20. Important features of cytochrome P450 enzymes  8. Certain types of CYP450 exist in the  mitochondria and use NADP‐linked flavoprotein called adrenodoxin reductase, and iron‐sulfur  containing protein adrenodoxin.g p 9 Th t i li id i l h h tid l h li9. They contain lipids, mainly phosphatidylcholine. 10.Most enzymes are inducible.
  21. 21. Important features of cytochrome P450 enzymes  11.Certain types of CYP450 are involved in the  metabolism of carcinogens e.g. CYP1A1. CYP1A1 metabolize polycyclic Aromatic  Hydrocarbons (PAH) Smokers have high levels of these enzymes 12.They are polymorphic proteins
  22. 22. Polymprohism of CYPPolymprohism of CYP450 • Polymorphic forms have different kinetic  properties e.g., CYP2D6.p p g CYP2D6 b li d b i i• CYP2D6 metabolizes debrisoquin (antihypertensive) and sparteine (antiarrythemic) – Extensive metabolizers (rapid clearance)Extensive metabolizers (rapid clearance) – Poor metabolizers (slow clearance)
  23. 23. Phase II reactionsPhase II reactions • Glucuronidation • Uses UDP‐GlucuronateUses UDP Glucuronate – Enzyme gucuronyl transferase S b i l d b i id ili– Substrates include: benzoic acid, aniline,  meprobamate, phenol, steroids.
  24. 24. Phase II reactionsPhase II reactions • Sulfation – Uses adenosine‐3‐phospho‐5‐pyrophosphate  (PAPS) as sulfate donor( ) Substrates include: alcohols arylamides steroids– Substrates include: alcohols, arylamides, steroids,  phenols.
  25. 25. Phase II reactions • Sulfation
  26. 26. Phase II reactionsPhase II reactions j i i h l hi ( )• Conjugation with glutathione (GSH) – Uses glutathione (γ‐glutamyl‐cysteine‐glycine). – The reaction is catalyzed by glutathione‐S‐y y g transferase. – Glutathione has other important functions • Decomposition of H2O2p • Important intracellular reductant • Amino acid transport in the kidney
  27. 27. Phase II reactions • Conjugation with glutathione (GSH)• Conjugation with glutathione (GSH)
  28. 28. Phase II reactions • Conjugation with glycine
  29. 29. Phase II reactionsPhase II reactions • Acetylation – Uses acetyl‐CoA as acetate donor.y The reaction is catalyzed by acetyl transferase– The reaction is catalyzed by acetyl transferase. – Substrates include: • Isoniazid (anti‐tuberculosis)
  30. 30. Phase II reactionsPhase II reactions • Acetylation AC‐HN Sulfonamide  N‐acetyl sulfonamide 
  31. 31. Phase II reactionsPhase II reactions • Methylation – Uses S‐adenosyl‐methionine as methyl donor.y y The reaction is catalyzed by methyl transferase– The reaction is catalyzed by methyl transferase. – Substrates include: • Isoniazid (anti‐tuberculosis)