Xenobiotics aug 2013
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Lecture Presentation, Science and Medical students
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Semelhante a Xenobiotics aug 2013
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Xenobiotics aug 2013
- 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. 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. 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. Examples of phase I reactionsExamples of phase I reactions • Hydroxylation • DeaminationDeamination • Dehalogenation • Desulfuration • EpioxidationEpioxidation • Peroxygenation • Reduction
- 6. Examples of phase II reactionsExamples of phase II reactions • Conjugation with glucuronic acid • Conjugation with glutathioneConjugation with glutathione • Sulfation • Acetylation • MethylationMethylation
- 7. Examples of phase I reactions • Hydroxylation B PhenolBenzene Catechol Aniline Parahydroxy aniline
- 8. Examples of phase I reactions • OxidationOxidation BenzaldehydeToluene Benzoic acidBenzaldehydeToluene Benzoic acid
- 9. Examples of phase I reactions • Oxidation i idMuconic acid Catechol β Ketoadipic acidβ‐Ketoadipic acid + Succinic acidAcetyl‐CoA
- 10. Examples of phase I reactions • Oxidation Salicylic acid Gentisic acid Homogentisic acidPhenylacetic acid
- 11. Examples of phase I reactions • Concomitant oxidation‐reduction p‐Nitrobenzaldehyde p‐Aminobenzoic acid
- 12. Examples of phase I reactions • Deamination A i iArginine
- 14. Examples of phase I reactionsExamples of phase I reactions • Hydroxylation • DeaminationDeamination • Dehalogenation • Desulfuration • EpioxidationEpioxidation • Peroxygenation • Reduction
- 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. 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. 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. 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. 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. 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.
- 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. 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. 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.
- 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. Phase II reactions • Conjugation with glutathione (GSH)• Conjugation with glutathione (GSH)
- 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. Phase II reactionsPhase II reactions • Acetylation AC‐HN Sulfonamide N‐acetyl sulfonamide
- 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)