Detoxification companion-doc

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Overview of the detoxification and biotransformation processes, factors that influence them, and case studies.

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  • Individual responses to detoxification
  • Detoxification companion-doc

    1. 1. Laboratory Markers of Toxins and Detoxification Dr. Eve Bralley and Dr. Elizabeth Redmond
    2. 2. Introduction <ul><li>Humans are constantly exposed to exogenous and endogenous toxins. </li></ul><ul><li>Detoxification is the process of transforming and removing xenobiotics. </li></ul><ul><li>Biotransformation occurs in steps I and II </li></ul><ul><li>Detoxification and biotransformation have their own energy, nutrient and regulatory requirements </li></ul>
    3. 3. Classes of Toxins and Methods of Detoxification Figure 1
    4. 4. http://www.alternative-therapies.com/at/web_pdfs/ifm_proceedings_low.pdf The Proceedings From the 13th International Symposium of The Institute for Functional Medicine Managing Biotransformation: The Metabolic, Genomic, and Detoxification Balance Points
    5. 5. Detection of Toxic Burden <ul><li>Ammonia burden </li></ul><ul><ul><li>Citrate, isocitrate, cis-aconitate </li></ul></ul><ul><ul><li>Orotate </li></ul></ul><ul><li>8-OH-dG </li></ul><ul><li>p -hydroxyphenyllactate </li></ul><ul><li>2-Methylhippurate </li></ul><ul><li>Dysbiosis markers </li></ul>
    6. 6. Additional Markers of Toxicant Exposure <ul><li>Urinary glucarate </li></ul><ul><ul><li>Phase I and II upregulation </li></ul></ul><ul><ul><li>herbicide, fungicide, petrochemical, alcohol and drug exposure </li></ul></ul><ul><li>Urinary benzoate </li></ul><ul><ul><li>Glycine conjugation </li></ul></ul>
    7. 7. Detection of Toxic Burden <ul><li>Porphyrins </li></ul><ul><li>Heavy Metals </li></ul><ul><ul><li>Whole blood, RBC, serum </li></ul></ul><ul><ul><li>Urine </li></ul></ul><ul><ul><li>Hair </li></ul></ul>
    8. 8. Phases of Detoxification <ul><li>Phase I: </li></ul><ul><ul><li>primarily cytochromes </li></ul></ul><ul><ul><li>addition of functional groups </li></ul></ul><ul><li>Phase II: </li></ul><ul><ul><li>conjugation reactions </li></ul></ul><ul><ul><li>attaches a water-soluble moiety </li></ul></ul><ul><li>Phase III: </li></ul><ul><ul><li>antiporter system </li></ul></ul>
    9. 9. Intermediate Metabolite Toxins Phase I (Cytochrome P450) Reactions: Oxidation Phase II (Conjugation Pathways) Sulfation Amino Acid conjugation Glucronidation Glutathione Metnhylation ROS Cell damage Free Radicals Antioxidants: Phytonutrients Vitamin C, E Minerals Excretion: Blood Urine Feces Phase II Nutrients : Glycine NAC B vitamins Phase I Nutrients : B vitamins Glutathione Flavanoids
    10. 10. Phase I <ul><li>Operates via Cytochrome P450 enzymes (Cyp) </li></ul><ul><li>Bioactivation – adds an attachment site to the toxin - Requires NADH (from niacin) </li></ul><ul><li>Can result in a more toxic toxin </li></ul><ul><li>Generates reactive oxygen species – thus ensuring antioxidant status is important </li></ul>
    11. 11. Phase I - Cyp Liver Enzymes P450 Enzyme Percent of Total Substrates Cyp3A4,5 29% Testosterone, cyclosporine Cyp2C8,9,18 18% Warfarine, R-mephenytoin Cyp1A2 13% Cafeine, aflatoxin B1 Cyp2E1 6% Ethanol, Carbon tetrachloride Cyp2A6 4% Coumarin
    12. 12. Phase II <ul><li>Products of phase I detoxification are further metabolized </li></ul><ul><li>Water soluble molecules are added creating inactive products called conjugates that are excreted in bile and urine </li></ul><ul><li>Conjugases </li></ul><ul><ul><li>Sulfation </li></ul></ul><ul><ul><li>Glucuronidation </li></ul></ul><ul><ul><li>Amino acid conjugation </li></ul></ul><ul><ul><ul><li>glycination </li></ul></ul></ul><ul><ul><li>Glutathione conjugation </li></ul></ul><ul><ul><li>Methylation </li></ul></ul><ul><ul><li>Acetylation </li></ul></ul>
    13. 13. Glutathione and Sulfate Conjugate Formation
    14. 14. Phase I and II Enzyme Induction <ul><li>Mono-functional inducers </li></ul><ul><ul><li>These elevate Phase II enzymes (such as glutathione S-transferases, NAD(P)H:quinone reductase, UDP-glucuronosyl-transferases) in various tissues without significantly raising the Phase I enzyme </li></ul></ul><ul><ul><li>Examples: cigarettes, charred meats, glucocorticoids, </li></ul></ul><ul><li>Bi-functional inducers </li></ul><ul><li> These induce both Phase I and Phase II enzymes </li></ul><ul><li>of xenobiotic metabolism. </li></ul><ul><li>Examples: flavonoids, garlic, rosemary, soy, cabbage, polycyclic aromatic hydrocarbons </li></ul>
    15. 15. Use of Challenge Compounds to Evaluate Phases of Detoxification
    16. 16. Caffeine Clearance <ul><li>200 mg dose </li></ul><ul><li>2 and 8 hour saliva collection </li></ul><ul><li>Phase I microsomal P450 mixed function oxidase activity </li></ul>
    17. 17. Caffeine Clearance <ul><li>If High: </li></ul><ul><ul><li>Liver is actively removing caffeine </li></ul></ul><ul><ul><li>Enzyme induction </li></ul></ul><ul><ul><li>Minimize exposure to environmental toxins </li></ul></ul><ul><li>If Low: </li></ul><ul><ul><li>Genetic polymorphisms or loss of liver function </li></ul></ul><ul><ul><li>Processing and degradation of foreign compounds is slower than normal </li></ul></ul><ul><ul><li>Xenobiotics could accumulate in adipose tissue </li></ul></ul><ul><ul><li>Drugs: cimetidine, amphetamines, grapefruit (narengenin) </li></ul></ul><ul><ul><li>Low exposure to toxins </li></ul></ul>
    18. 18. Acetominophen Biotransformation <ul><li>650 mg dose </li></ul><ul><li>Urinary acetaminophen sulfate and acetaminophen glucuronide </li></ul><ul><li>Sulfate and B-vitamin status </li></ul>
    19. 19. Aspirin Biotransformation <ul><li>650 mg dose </li></ul><ul><li>O-hydroxyhippurate </li></ul><ul><li>Glycine, pantothenic acid status </li></ul>
    20. 20. Conjugation Pathways Used for Specific Compounds
    21. 21. Phase I/II Ratios <ul><li>Bioactivation </li></ul><ul><li>Impairment in phase II conjugation could lead to accumulation of toxic intermediates </li></ul><ul><li>Supplement with antioxidant nutrients </li></ul><ul><ul><li>Free radicals </li></ul></ul><ul><ul><li>Cell injury </li></ul></ul><ul><ul><li>DNA modification </li></ul></ul><ul><ul><li>Haptens </li></ul></ul>
    22. 22. Factors that influence detoxification: <ul><li>Age </li></ul><ul><li>Gender </li></ul><ul><li>Diet and Lifestyle </li></ul><ul><li>Environment </li></ul><ul><li>Disease State </li></ul><ul><li>Genetic polymorphisms </li></ul><ul><li>Supplement use </li></ul><ul><li>Intestinal Health </li></ul>
    23. 23. Supporting Detoxification <ul><li>• Co-factors and Nutrients </li></ul><ul><ul><li>Nicain, B6, glycine, NAC </li></ul></ul><ul><li>Antioxidants/protective nutrients </li></ul><ul><ul><li>vitamin C and E, zinc, lipoic acid </li></ul></ul><ul><li>Phytonutrients can trigger the activity of gene response elements </li></ul><ul><ul><li>Sulforaphane from broccolli </li></ul></ul>
    24. 24. Polymorphysims <ul><li>There are many known polymorphysims that can affect detoxification. </li></ul><ul><li>Example of effects; </li></ul><ul><li>Felton, J.S. What do diet-induced changes in phase I and phase II enzymes tell us about prevetnion from exposure to heterocyclic amines? Journal of Nutrition, Oct 2006. 136(10); 2683-4S </li></ul><ul><li>http://jn.nutrition.org/cgi/content/full/136/10/2683S </li></ul>
    25. 25. Case 1 <ul><li>Case 1 </li></ul><ul><li>52 year old man </li></ul><ul><li>Suffers from occasional abdominal cramps, fatigue, and malaise. </li></ul>
    26. 26. Case 1
    27. 27. Case 2 <ul><li>50 year old female </li></ul><ul><li>Fatigue, depression, joint pain, IBS symptoms </li></ul>
    28. 28. Case 2 Detoxification Capacity Profile
    29. 29. Case 2 Amino Acid Profile – 20 - Plasma
    30. 30. Case 2 Organix SM Profile GIfx
    31. 31. Case 3 <ul><li>49 year old male </li></ul><ul><li>Depression, fatigue, headaches, overweight </li></ul><ul><li>Moderate alcohol intake </li></ul>
    32. 32. Case 3 Detoxification Capacity Profile
    33. 33. Amino Acid Profile – 20 - Plasma
    34. 34. Elements Erythrocytes/Whole Blood OrganixSM Profile
    35. 35. Case 4 <ul><li>41 year old, painter </li></ul><ul><li>Environmentally sensitive </li></ul>
    36. 36. Case 4 Detoxification Capacity Profile
    37. 37. Case 4 Organix SM Profile GIfx
    38. 38. Thank You For questions on these or any testing please go to www.metametrix.com or call at 800-221-4640

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