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Decoding Human Drug Metabolism: P450 Profiling for Personalized Therapy

Unravel the complexity of human drug metabolism and its impact on individual response to medication. Explore how metabolic signatures influence drug interactions, adverse reactions, and personalized therapy. Understand the role of P450 enzymes in detoxification and drug clearance.

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Decoding Human Drug Metabolism: P450 Profiling for Personalized Therapy

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  1. Are humans really are what they eat? Complexity of human drug metabolism by Olga Trubetskoy

  2. Terminology • Metabolism: (Gk: metabole: change) • Xenobiotics: xeno (Gk: foreign)… biotics • Inhibition (Latin inhibitus, ): to prohibit from doing something • Induction (Latin inducere): to induce: to call forth or bring about by influence or stimulation • Cytochrome P450s (CYPs)

  3. P450s is a weapon in plant-animal chemical warfare “We are continually under threat from chemical warfare in the guise of foreign compounds in our diet and environment, odorants, drugs and our bodies’ own waste chemicals. CYP450s are a vital part of defense system which reduce the toxicity of potentially damaging chemicals and facilitate their excretion” - B. Burchell

  4. Drug metabolism process (defense mechanism against plants’ toxins) P450 Food Toxin

  5. Individual’s metabolic signature • An individual exposure to food and environmental compounds leaves a “metabolic signature” in our body, changing the way we are interacting with our environment • Many factors, including genetic, environmental, in uterus exposure, life style, diet and eating habits contribute to a “metabolic fingerprint map” unique for each individual organism • This “metabolic signature” may serve as a basis for the personalized drug therapy

  6. Why is it important to know you “metabolic signature”? • Adverse reactions to prescription drugs are killing about 106,000 Americans each year -- roughly three times as many as are killed by automobiles. • This makes prescription drugs the fourth leading killer in the U.S., after heart disease, cancer, and stroke • What is behind adverse drug reactions + +

  7. Why do you need to know your metabolic profile (“metabolic signature”)? • This information may save your life!!!!! • Drug-drug and drug/food interactions are one of the leading cases of patients’ mortality • What drugs to prescribe/avoid and dose • What combination of drugs to avoid • How your behavior affects your metabolism • Do you really need “a pill”? Start with P450 profiling

  8. Get to know your P450s: body’s own biochemical weapon • “Weapon’s” design:

  9. P450s: where they are involved • Metabolism of xenobiotics*: • toxification • detoxification • production of intermediate metabolites (active, inactive, toxic) * xenobiotics - non-biological compounds prevalent in the environment, including drugs, nutrients, herbal and plant food components, odorants, toxins, carcinogens and mutagens

  10. Main P450s in drug metabolismMajor classes of “weapons” (P450s) Families CYP1 CYP2 CYP3 CYP3A, 2D6, 2C9, 2C19, 1A2, 2E1

  11. Variability of drug clearance (how fast drug is eliminated)

  12. Simulated effect of P450 induction

  13. Simulated effect of P450 inhibition

  14. Do we have control over our own weapons?Levels of complexityin drug metabolism response: • Genetics • Epigenetic • In uterus exposure • Age, sex, disease • Diet and nutrition • Exposure to environmental toxins • Psychological factors

  15. Control over sources of variability (on/off switch programming) • Genes - individual, ethnic (initial conditions) • Physiology: • age, sex, diseases (uncontrolled conditions) • nutrition and diet, alcohol and smoking, style of life (partial control) • Environment (environmental toxins, mutagens carcinogens) (partial control?) • Psychology– anything will work in 40% cases (placebo effect) – may be?

  16. Genetics: P450 polymorphism CYP2D6 PM (poor metabolizer) - inactive or absent enzyme EM (extensive metabolizer) - at least 1 functional allele UM (ultrarapid metabolizer) - multiple copies (up to 13) of CYP2D6 gene Frequency of PM phenotype: Caucasian ~12 % African-American ~1 - 3% Asian <1 % Frequency of EM phenotype: Ethiopian ~13 % Spanish ~3.5 %

  17. Can you influence your genes? The most interesting example: high expression of CYP2D6 in many persons of Ethiopian and Saudi Arabian origin. 2D6 is not inducible, so these people have developed a different strategy to cope with the (presumed) high load of toxic alkaloids in their diet - multiple copies of the gene (up to……) Changing the diet (moving to Sweden) changed their CYP2D6 phenotype to (not genotype). Effect of fast metabolism may be dual - many antidepressants and neuroleptics are quickly become ineffective. Conversely, prodrugs will be extensively activated - codeine will be turned into morphine almost immediately. 13 1 Others: through induction CYP2C9, 2D6, 2C19, 3A4

  18. Interplay between nuclear receptors (NR), their ligands and CYP450s P450 X, E XO, EO Xeno-, Endo- biotics P450 genes metabolites On off NRs On off Other genes

  19. How dietary composition can modulate on/off switch • Unlike that of other animal species, the human diet is extremely variable among individuals. • The compositions of diets vary according to availability, religion and the method of preparation

  20. Which P450 enzymes are being affected

  21. Does it matter if you had a glass of coffee, grapefruit juice or milk for breakfast? What else? • Spices (saffron, cumin, ginger) • Flavonoids (soy, red wine) • Fruits (bergamottin – grapefruit juice) • Other herbs: St. John’s Wort • Cruciferable vegetables (sprouts, cabbage) due to a presence of indols • Caffeine • Smoking (benzopyrene)

  22. CYP1A induction by flavonoids 1 bottle 2 glasses Curry Red wine (good wine stored in brown bottle)

  23. Food/spices modulate P450 activity CYP3A4 Onion , garlic Hot pepper CYP2E1 Root beer

  24. Cooking style modulates P450 activity Individuals who ate a charcoal-broiled 8-ounce hamburger at lunch and a 6-ounce steak for dinner each day for 4 days had >80% lower plasma concentrations of phenacetin compared with those who ate their usual home diet A high-protein–low carbohydrate diet for 2 weeks increases the metabolism of caffeine and aminopyrine

  25. Grapefruit juice modulates (inhibits) CYP3A4 activity Bergamottin (present in grapefruit skin only)

  26. Diet modulate P450 activity

  27. Alcohol modulates P450 activity • Alcohol (dual effect– beneficial from red wine flavonoids and induction from ethanol exposure) • Alcohol – induced toxicity of acetaminophen (Tylenol) Acetaminophen in small amounts is metabolized by glucuronidation and sulfation. Larger ingestions result in production of a toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) by P450. The NAPQI is normally detoxified by glutathione. However, chronic alcoholism depletes glutathione, and also induces P450 to increase toxicity. Thus, previous chronic alcohol ingestion increases the risk for acetaminophen toxicity.

  28. Smoking modulates P450 activity • Polycyclic hydrocarbons in cigarette smoke induce the metabolism of CYP1A substrates as a result of CYP1A induction • The average content of CYP1A in the liver biopsies from smokers (16.3 pmol/mg of protein) was significantly higher than that from nonsmokers (4.7) • Theophylline, caffeine, fluvoxamine, clozapine, and olanzapine clearance is significantly increased in smokers compared with nonsmokers

  29. Herbal supplements modulate P450 activity • St. John’s Wort (Hypericum perforatum) extracts, preparations that are used in the treatment of depression, inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 • Ginseng (CYP1A1, 1A2, 1B1)-inhibition • The Licorice Root derived Isoflavan Glabridin inhibits P450s 3A4, 2B6, and 2C9

  30. Multiple drug interactions modulate P450 activity A63 year old man receiving medication for major depression showed he boarded a plane in Toronto to fly to London. On arrival he was unrousable. In his Carry-on bag he had Mefadazone (for depression), Ketoconazole (for fungal infection) and Triazolam (an antipsychotic also used for insomnia). All three of these drugs bind to CYP3A4. Ketoconazole inhibits CYP3A4 and caused the other two drugs to become overdosed during 6 hr flight (sitting still is a factor). Ketoconazole CYP3A4 + + Triazolam Mefadazone Overdose

  31. Do our eating (and other) habits leave marks (metabolic signatures) in our drug metabolism landscape?

  32. Prescriptions based on genotype or phenotype? • E.g., do we need to know only initial conditions (your genes) or the final picture (on/off switch)? • Can we regulate this complex picture? • To a what degree? • And if we can, then….

  33. Can one do things right just for himself? • Presence of drug metabolites in soil and underground waters (contamination) • Global environmental exposure • Are all these factors triggers for human adaptation?

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