Functions

• Xenobiotic metabolism (especially lipophilic substances)
• biosynthesis of chemical signalling molecules such as steroids and fatty acid derivatives
  • Thromboxane (product of the metabolism of arachidonic acid), vasoconstrictor
  • Prostacyclin (product of the metabolism of arachidonic acid), vasodilator
• Detoxification of endogenous molecules such as steroids
• Generation of prostaglandins
• Biosynthesis of complicated defense chemicals
  • eg erythromycin
• metabolism of drugs/exogenous toxins (espeically CYP3A4, Cyp1A1, Cyp1A2, Cyp2D6, and the Cyp2C enzymes)
• They add a reactive group, such as hydroxyl radical, to the molecule being processed
• The process requires
  • Oxygen
  • Misc. cofactors: NADH, riboflavin, niacin, magnesium, iron, certain indoles from cruciferous vegetables
• Danger: if these reactive molecules are not further metabolized by Phase II conjugation, they may cause damage to proteins, RNA, and DNA within the cell.

Distribution

• Liver
• Organs of entry: gut, lung. skin, kidney/bladder
• steroidogenic tissues
• brain & vasculature (expression P450s)
• every tissue

Influences on them

• Ketoconazole – fairly non-selective inhibitor of P450s, perturbing mammalian steroid metabolism
• St. John's Wort
• Narginen – flavonoid high in grapefruit juice; inhibits first-pass metabolism of many drugs detoxified through the Cyp3A4 enzyme-antiporter system in the intestine (tips of villi).
  • See notes to Liska
• Silymarin - has been helping me, inhibits [?]
• Artichoke (related to Silymarin) stimultes bile
• Burdock
• NAC (N-Acetylcysteine) "not everybody tolerates NAC well."— Steven Shackel
• Dandelion (I believe I reacted to this when I tried it in '97.)
• Curcumin (the compound that gives turmeric its yellow color) inhibits phase I while stimulating phase II.
• The bioflavonoid quercetin inhibits lipoxygenase (good!) and also sulfotransferase [not so good? — look this up]*

Family Cyp1: drug metabolism

1. Induced by aromatic hydrocarbons
2. Family 1A appears to be involved particularly in dealing with products of combustion
   1. inducible by polycyclic hydrocarbons, some of which are found in cigarette smoke and charred food.
   2. they activate compounds to carcinogens
3. Cyp1A1
   
4. Cyp1A2
   1. demethylates caffeine; rate of demethylation can show if a person has been induced by exposure to polycyclic aromatic hydrocarbons
   2. inhibited by
      1. Piper methysticum (Kava)
         1. Hopkins, Ursula K (Pharm.D, Clinical Toxicology Fellow, Maryland Poison Center), Dietary Supplements: Potential Risks in MSHP PHARMASCRIPT May 2000 (Vol.23 No. 5).
      2. possibly: Valerian and Gingko biloba, chili pepper and black peppers may inhibit CYP 1A2 enzymes (see Hopkins.)
      3. grapefruit* [check this]
5. Cyp1B1

Family Cyp2 (largest family in humans): drug & steroid metabolism

1. Cyp2E1
   1. oxidation of ethyl alcohol to acetaldehyde
   2. detoxifies many of the small carbon-chain molecules, including ketone bodies, that result from gluconeogenesis and the breakdown of fatty acids.
   3. energy metabolism
   4. increased by starvation (see notes to Liska)

Family Cyp3: drug metabolism

1. Cyp3A4
   1. "most abundantly expressed P450 in the liver"
   2. high concentrations at tip of intestinal villi as well as liver
   3. one of the P450s responsible for metabolism of drugs/exogenous toxins
   4. inhibited by
      1. ketoconazole — very strong effect
      2. progesterone (See notes to Liska)
      3. Hypericum perforatum (St. John's Wort)
         1. Moore et al show induction
         2. However Ohrbach shows inhibition
         3. Budzinski JW, Foster BC, Vandenhoek S, et al. An in vitro evaluation of human cytochrome P450 3A4 inhibition by selected commercial herbal extracts and tinctures, Phytomedicine 2000;7(4): 273-282. (See abstract at bottom of this page.)
         4. Hopkins
      4. Hydrastis () Budzinski et al.
      5. Piper methysticum (Kava)
         1. Budzinski et al.
         2. Hopkins
      6. Grapefruit
         1. Hopkins
         2. See notes to Liska
      7. antifungals and hydrocortisone*
      8. Cloves, ginger, oregano, sage, thyme, turmeric, chamomile, echinacea, feverfew, Siberian ginseng, goldenseal, and soybean: Effects of Natural Health Products on Cytochrome P-450 Drug Metabolism. B. C. FOSTER1, S. VANDENHOEK2, J. HANNA2 , M. H. AKHTAR3, and A. KRANTIS2. Health Canada, Ottawa, Ontario1, Digestive Diseases Research Group, University of Ottawa2, Ottawa, Agriculture and Agri-Food Canada3, Guelph, Ontario.
         1. See Poster # AAFC 050 from the Food Science at Work Conference, University of Guelph, (Ontario, Canada) September 16 & 17, 1999.
         2. Another report of the same conference on the site of CATIE (Community AIDS Treatment Information Exchange)

   5. Some substrates:
      1. Acetaminophen -- mixed function oxidase system, specifically cyp2E1. See Acetaminophen Poisoning.
      2. Codeine
      3. Erythromycin
      4. Lidocaine

Family Cyp4: arachidonic acid or fatty acid metabolism

Faamily Cyp5: Thromboxane A2 synthase

1. Inhibitors: ketoconazole, itrconazole, erythromycin

Family Cyp7A: the first and rate-liminting step of bile acid synthesis

Family Cyp7B: brain-specific form of 7-alpha hydroxylase. Catalyzes the synthesis of neurosteroids

Family Cyp8A: prostacyclin synthase

Family Cyp8B: bile acid biosynthesis

Family Cyp11: steroid biosynthesis

Family Cyp17: steroid biosynthesis

Family Cyp19: aromatase that makes estrogen

Family Cyp21: steroid biosynthesis

Family Cyp24: Vitamin D degradation

Family Cyp26: retinoic acid hydroxylase

Family Cyp27A: bile acid biosynthesis

• CYP27A1 in Vitamin D metabolism, catalyzes the conversion of cholecalciferol to 25(OH)D(3) and of 25(OH)D(3) to calcitriol

Family Cyp27B: Vitamin D3 1-alphya hyroxylase activates vitamin D3

Family Cyp46: cholesterol 24-hydroxylase

Family Cyp51: cholesterol biosynthesis, lanosterol 14-alpha demethylase. "the target of the triazle antifungal drugs like ketaconazole." (Nelson)

• *posting on AMALGAM email list (see directions for access)
• My page Detoxification
• My page Progesterone
• Essential P450s - Heme thiolate proteins and their place in the biosphere. A brief but comprehensive introductory survey offered as a tutorial for a Pharmacology course.
• The Detoxification Enzyme Systems by DeAnn J. Liska, PhD. Brief survey of Phases I, II and III, with extensive references.
• Cytochrome P450s in humans, by Dr. David Nelson, University of Tennessee, Memphis – moderately detailed descriptions of the P450s whose functions have been identified.
• Cytochrome P450 –a brief overview, from MCS - Allergy Help . A somewhat spotty and chaotic site, but it has a search engine.
• Cytochrome P450 Homepage - the website of the Committee for Standardized Cytochrome P450 Nomenclature, maintained by Dr. David Nelson. Updated frequently.
• Cytochrome P450 Drug Interaction Table., by D.A. Flockhart.
• Aromatase Cytochrome P450 and in Situ Estrogen Production - conversion of androgens to estrogens
• Xenobiotic-Metabolizing Enzymes - by Mendelsohn et al, chapter "Xenobiotic-Metabolizing Enzymes in Biomarker Research," Biomarkers and Occupational Health: Progress and Perspectives (1995) Joseph Henry Press / Nat'l Academy Press, p 239. Table of 19 enzymes and their co-substrates.
• P450s and St. John's Wort
  • Inhibits CP3A4
  • Induces CP3A4
• Expert Protein Analysis System database's entry on CYP 3A4
• from MiDobs@INTERNETWIS.COM
• message-ID: <199902281552.SM00141@default>
• Sun, 28 Feb 1999 14:50:18 -0800