metabolism.pptx @78768765213780075#@2790)732168)(632#(9/

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1. Metabolism , or Biotransformation, the chemical conversion of toxicants into compounds which are easier to eliminate. In case of xenobiotics metabolism is known as detoxification

2. Xenobiotic biotransformation is the process of converting lipophilic (fat soluble) chemicals , which are readily absorbed from the gastrointestinal tract and other sites, into hydrophilic (water soluble) chemicals , which are readily excreted in urine or bile.

3. Converting lipophilic to water soluble compounds Xenobiotic Reactive intermediate Conjugate Phase I - Activation Phase II - Conjugation Excretion Lipophilic (non-polar) Water soluble (polar)

4. BENZENE PHENYL SULPHATE

5. TOXICANT ABSORPTION

6. 8 toxicant may be: As raw material May be synthetic form May be semi-synthetic form Taken as nutrition only Taken as essential body compounds, like VITAMINS

7. toxicant

8. The metabolism of toxicant leads to, The active toxicant is converted in to inactive metabolites & excreted Active metabolites from equally active metabolites Active metabolites from inactive drug (prodrug) Conversion in to toxic substances

9. Active to inactive form

10. esterase Cocain benzoylecgonine p450 Phenytoin 4-hydroxy phenyl gst Aflatoxin2,3-epoxide 8 glutathionyl- 9hydroxyaflatoxin ugt Morphine morphine-3-glucuronide

11. Active to active

12. P450 CODEINE MORPHINE ESTERASE HEROIN MORPHINE P450 THIOBARBITAL BARBITAL

13. INACTIVE TO ACTIVE

14. REDUCTASE CHLORAL HYDRATE TRICHLOROETHANOL REDUCTASE PRONTOSIL SULFANILAMIDE

15. INACTIVE TO TOXIC

16. P450 ACETAMINOPHEN N-ACETYL-P-BENZO QUININE IMINE P450 MALATHION MALAOXAN P450 ACETYLHYDRAZINE ACETYLCARBONIUM ION

17. Where metabolism occur: • All tissues have the ability to biotransform toxicants • The liver is ideally placed to intercept natural ingested xenobiotics and has a major role in biotransformation • GIT, Lungs, Skin and Kidneys,PLASMA

18. W. Tassaneeyakul Lipophilic toxicant Hydrophilic metabolite Biotransformation Metabolite excreted

19. The biotransformation of xenobiotics is catalyzed by various enzyme systems that can be divided into four categories based on the reaction they catalyze: 1. Hydrolysis (e.g., carboxylesterase) 2. Reduction (e.g., carbonyl reductase) 3. Oxidation (e.g., cytochrome P450) 4. Conjugation (e.g., UDP-glucuronosyltransferase)

20. BIOTRANSFORMATION REACTIONS

21. PHASE 1 REACTIONS PHASE II REACTIONS

22. PHASE I REACTIONS INTRODUCTION OF REACTIVE,POLAR FUNCTIONAL GROUP HYDROXYL AMINO CARBOXYL EPOXIDE HYDROXALAMINE SULFHYDRYL

23. PHASE II REACTIONS Endogenous substrate like glucuronic acid , sulfuric acid , acetic acid , or an amino acid combines with the newly incorporated functional group to form a highly polar conjugate. These are known as synthetic reactions.

24. Phase I and II reactions are compartmentalized Phase I Phase II

25. Role of liver in biotransformation

26. Kidney Urine Drug molecule More hydrophilic metabolite Conjugate Bile Feces Intestines I II TOXICANT

27. Toxicant metabolism

28. W. Tassaneeyakul Relative abundant of human XMEs

29. Phase I

30. Phase II

31. P450s: body’s own biochemical weapon “Weapon’s” design:

32. CYP

33. In vertebrates the liver is the richest source of CYP and is most active in the monooxygenation of xenobiotics. CYP and other components of the CYP-dependent monooxygenase system are also in the skin , nasal mucosa , lung , and gastrointestinal tract . In addition to these organs, CYP has been demonstrated in the kidney , adrenal cortex and medulla , placenta, testes , ovaries , fetal and embryonic liver , corpus luteum , aorta , blood platelets , and the nervous system . In humans, CYP has been demonstrated in the fetal and adult liver , the placenta , kidney , testes , fetal and adult adrenal gland , skin , blood platelets , and lymphocytes

34. CYP3A4 : is responsible for metabolism of largest number(>50%)of toxicants. In addition to liver , these isoforms are present in kidney as well.

35. CYP2D6: this is the next most important CYP isoform which metabolizes nearly 20% toxicant including tri-cyclic antidepressants, neuroleptics, antiarrhythmics ,beta blockers and opiates. INHIBITION OF THIS ENZYME BY quinidine RESULTS IN FAILURE OF CONVERSION OF CODEINE TO MORPHINE<<<<>>>>>analgesic effect of codeine is lost.

36. 44 CYP2C8 : are important in the biotransformation of >15 commonly used TOXICANTS including phenytoin and warfarin . CYP2C19 : metabolizes >12 frequently used toxicants including OMEPERAZOLE,lansoprazole.

37. Phase I reactions

38. Oxidation Hydroxylation (addition of -OH group) N- and O- Dealkylation (removal of -CH side chains) Deamination (removal of -NH side chains) Epoxidation (formation of epoxides ) Oxygen addition ( sulfoxidation , N-oxidation) Hydrogen removal

39. Alcohols, aldehydes , and ketones are oxidized by a number of enzymes, including alcohol dehydrogenase , aldehyde dehydrogenase , AKRs (such as those with dihydrodiol dehydrogenase activity), the molybdenum-containing enzymes , aldehyde oxidase , and xanthine dehydrogenase / oxidase , and cytochrome P450 .

40. HYDROXYLATION

41. epoxidation

42. Reduction Hydrogen addition (unsaturated bonds to saturated) Oxygen removal

43. Biotransformation of Xenobiotics... 58 Phase I: Reductions Azo reduction N=N to 2 -NH 2 groups eg: prontosil to sulfanilamide Nitro reduction N=O to one -NH 2 group eg: 2,6-dinitrotoluene activation N -glucuronide conjugate hydrolyzed by gut microflora Hepatotoxic compound reabsorbed

44. Nitro Reduction

45. Azo Reduction Microsomes and cytosol

46. Azo- and nitro- reduction

47. Hydrolysis C O I װ Splitting of C-N-C (amide) and C-O-C (ester) bonds

48. Epoxide Hydrolase

49. Ester Hydrolysis Microsomes and cytosol Enalaprit

50. Phase II reactions

51. W. Tassaneeyakul Cofactors for Phase II (Source: Parkinson 2001)

52. in some newborns the liver may lack the enzyme, glucuronyl transferase which conjugates bilirubin, a water-insoluble hemoglobin breakdown product; as a result, large amounts of bilirubin accumulate on the plasma albumin (hyperbilirubinemia); if such infants are given sulfonamides or vitamin K which displace the bilirubin from albumin, enough bilirubin can be freed in a short period of time and enter the brain to cause kernicterus (widespread destruction of nerve cells in the brain).

53. CATS ALSO LACK NAT ENZYMES PIGS DEFICENT IN SULFATE CONJUGATION

54. An extreme example of a difference in rates of metabolism is afforded by the drug oxyphenbutazone. In the dog it is rapidly metabolized and has a half-life of around 30 min , in several other species such as the rat, rabbit and monkey the half-life is between 3 and 6 h, whereas in humans metabolism is very slow and therefore the drug has a half-life of about 3 days.

55. Fish have a relatively poor ability for oxidative metabolism compared with the commonly used laboratory animals such as rats and mice. Insects such as flies have microsomal enzymes, and these are involved in the metabolismof the insecticide parathion to the more toxic paraoxon

56. Considerable species differences exist in the conjugation of aromatic carboxylic acids with amino acids. A number of amino acids may be utilized, although conjugation with glycine is the most common route and occurs in most species except some birds, where ornithine is the preferred amino acid.

57. Humans and Old World monkeys utilize glutamine for conjugation of arylacetic acids and in the pigeon and ferret taurine is used. Reptiles may excrete ornithine conjugates as well as glycine conjugates, and some insects utilize mainly arginine.

58. Aromatic acids may also be excreted as glucuronic acid conjugates, and the relative importance of glucuronic acid conjugation versus amino acid conjugation depends on the particular species and the structure of the compound. Herbivores generally favour amino acid conjugation, carnivores favour glucuronide formation, and omnivores, such as man, utilize both routes of metabolism.

59. oxidation reaction which shows variation in human populations is the oxidation of ethanol. This has been shown to be significantly lower in Canadian Indians compared with Caucasians, and thus the Indians are more susceptible to the effects of alcoholic drinks. The rate of metabolism in vivo in Indians is 0.101 g/kg/h compared with 0.145 g/kg/h in Caucasians. This seems to be due to variants in alcohol dehydrogenase, although differences in aldehyde dehydrogenase may also be involved. Variants of alcohol dehydrogenase resulting in increased metabolism have also been described within Caucasian and Japanese populations .

60. Foods That Affect Cytochrome P450 Broccoli Cabbage Other Cruciferous Vegetables Spinach Leeks Onion Garlic Parsley Grapefruit Fried and charcoal broiled foods Smoked fish or meat Ham Sausage

61. Diet : may alter hepatic cytochrome P 450 activity Smoked foods (polycyclic aromatic hydrocarbons) increase CYP1A activity (Kall & Clausen 1995) Cruciferous vegetables (brussels sprouts, cabbage, broccoli): alter activity of selected CYP isoenzymes Indole-containing vegetables (cabbage, cauliflower) upregulate CYP1A (Pantuck et al., 1989) Isothyocyanate-containing vegetables (watercress) inhibit CYP2E1 (Kim & Wilkinson 1996) Organosulfur compounds (garlic) inhibit CYP2E1 and induce CYP1A, CYP3A and phase II enzymes Grapefruit juice phytochemicals influence CYP3A activity Vitamins, spices

62. Fruit Juices and CYP450

63. Naturally Occurring Toxicants: Constituents Cholinesterase inhibitors: solanine in potatoes Cyanogenic glycosides: amygdalin in apple seeds Glucosinates: sinigrin in cabbage Protease inhibitors: protease inhibitors in soy beans Nitrites in green leafy plants Allergens: eg beta-lactoglobulin in milk, peanut proteins, soy protein

64. Naturally Occurring Toxicants: Contaminants Mycotoxins: aflatoxin in mouldy peanuts, vomitoxin in wheat Bacterial toxins:  botulinum  toxin and Staphylococcal toxin Seafood toxins: histamine, saxitoxin, domoic acid and tetrodotoxin Environmental Toxicants Food packaging residues: monomers of plastic resins Pesticide residues: herbicides, insecticides, fungicides; eg: malathion residues on fruit Heavy metals: lead, mercury, cadmium; eg: lead in vegetables; mercury in large ocean fish (eg. swordfish) Animal drugs: antibiotics, hormones; eg: penicillin in milk Radioisotopes: from soil or radioactive fallout

65. Grapefruit Juice: What’s the Story?

66. furancoumarin 6,7-dihydroxybergamottin

67. Garlic Allicin main ingredient Platelet aggregation inhibition Also has anti-hypertensive, anti-neoplastic, antilipemic, antibiotic effects SOME garlic preparations also induce CYP3A4.

68. Drug-Herb Interactions Types of Drug Interactions – Decreased bioavailability of drug ↓ Absorption (fibers, mucilage herbs, ↑ p-glycoprotein) ↑ Metabolism (↑ CYP 450) ↑ Elimination (laxative or diuretic herbs) – Increased bioavailability of drug ↑ Absorption (Ginger, Cayenne, Black Pepper) ↓ Metabolism (↓ CYP 450, eg. Grapefruit Juice) ↓ Elimination (Licorice- anti-diuretic)

69. Pomegranate juice appears to cause interactions in a manner similar to grapefruit juice based on preliminary evidence. But there is conflicting reports on its interactions. Until more is known, err on the side of caution. Advise patients not to drink pomegranate juice if they are taking drugs metabolized by CYP3A4 Pomegranate juice