The Importance of Methionine Metabolism in Comprehensive Detoxification The Importance of Methionine

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Transcript of The Importance of Methionine Metabolism in Comprehensive Detoxification The Importance of Methionine

  • The Importance of Methionine Metabolism in Comprehensive

    Detoxification and Health

    David Quig, PhD

  • Disclosure

    David Quig is the Vice President, Scientific Support, for Doctor’s Data, Inc.

  • David Quig, PhD

    Environmental Toxins

    • Centers for Disease Control and Prevention (C.D.C)

    “The epidemic of epidemics of CVD and immunological and neurological diseases is likely associated with environmental toxins [toxicants]”

    ATSDR/CDC/USPHS monographs on specific toxic metals

  • David Quig, PhD

    Multiple Assailants, Individual Victims

    • Knowledge of adverse effects have been based primarily on independent studies of SINGLE toxicants. (NIEHS)

    • Toxicants (metals, chemicals) can elicit independent, additive or synergistic toxic effects. (C.D.C.)

    • Individuals vary considerably in their sensitivity to toxicants and, susceptibility to toxic effects varies with age, gender, pregnancy status, nutritional status, total toxic load and genetics. (C.D.C.)

    Single Nucleotide Polymorphisms (SNPs)

    ATSDR/CDC Lead update(2007) Am J Clin Nutr(2009)89:425-30 Med Clin N

    Am(2005)89:721 Int J Res Pub Hlth(2011)8:629-47 Env Hlth Perspect(1995)103:1048

  • David Quig, PhD

    Endogenous Detoxification

    • Chemical entities (environmental toxicants and endogenously produced toxins, including gut derived)

    • Reactive oxygen species (ROS)

    • Methionine metabolism- methylation / transsulfuration

    • Toxic elements (intertwined effects, direct and epigenetic)

  • David Quig, PhD

    The GI Microbiome and Toxicology

    • The C.D.C. acknowledges that toxicokinetic models need to be revised to include the influence of the GI microbiome “pool.”*

    • Strong evidence that toxicant disruption of the GI microbiome crosses generations (e.g. “bad microbiome from grandma”)

    • Microorganisms that normally live in the GI tract perform many useful functions (train immune system, neurotransmitter production)

    • Promote the expression of hepatic CYPs (Phase I)

    • Detoxification of arsenic, lead, mercury and chemical entities

    • Convert a phytoestrogen precursor (hops) to an anti-inflammatory, cardioprotective compound

    • The metabolic activity of the GI microbiome rivals that of the liver!

    Env Hlth perspect(2011)119:A341-46 Env Hlth Perspect(2009)117:A199-205 *Personal communication: R.Dietert, PhD Toxicologist, Cornell University [4/5/14]

  • David Quig, PhD

    Detoxification of Organic Compounds: Endo- and Xenobiotics

    • PhaseI – oxidative activation

    • Phase II – conjugation

    • Phase III –unidirectional excretion

    • Optimal detoxification requires coordinated regulation of expression of genes encoding for enzymes in all three phases

    J Neurosci(2008)28:265-72 Drug Metab Dispos(2001)29:779-80

  • David Quig, PhD

    Phase I: Oxidative Activation • Cytochrome P450 enzymes (CYPs) add reactive & polar

    groups to lipophilic substrates → reactive electrophiles (oxidation, hydroxylation, or N-, O-, S-dealkylations)

    • Prosthetic heme is absolutely essential for CYP activities.

    • Heme biosynthesis (porphyrinogen pathway) requires Fe and Zn.

    Affected by anemias, and inherited enzyme defects

    Inhibited by Pb, Hg, As and chemical entities (specific urine porphyrin profiles)

    Drug Metab Rev(2011)43:1-26 Cell(2005)122:505-15 J Biol Org Chem (1997)2:411-17

  • David Quig, PhD

    Toxicants Inhibit Phase I Detoxification

    Toxicology in Vitro (2007)21:408-16 Molec Carcinogenesis (2000)28:225-35 Toxicol Letters(2004)148:153-8 Interdisip Toxicol(2013)6:159-84

    Eur J Pharmacol(2005)510:127-134

    Cytochrome P450 isozymes (CYPs)

    Xenobiotic

    Activated Xenobiotic

    Hg, Pb, Cd, As, Co, X Cr6, glyphosate, O-antigen (K. pneumoniae, P. aeruginosa)

  • David Quig, PhD

    Phase II: Conjugation

    • Conjugation of activated toxins to increase hydrophilicity (e.g. GSH, sulfation, acetylation or glucuronidation)

    • Catalyzed by broad-specificity transferases (glutathione S-transferases,UDP-glucuronosyl-transferases)

    • Cannot cross lipid membranes at a sufficient rate without specific ATP-dependent export transporters (Phase III)

    Drug Metab Rev(2011)43:1-26 Biofactors(2003)17:103-14 BBA(1999)1461:377-94

  • David Quig, PhD

    Phase II: Glutathione Conjugation

    Activated Xenobiotic

    GS-conjugates

    GSH

    Glutathione S-transferases

    Comp Biochem Physiol Clin Toxicol Pharmacol(2008)148:117-21 Molec Carcinogen(2000)28:225-35 Food & Chem Toxicol (2004) 42: 1563-71

    Pb, MeHg, Hg, Cd, As, Cr6, Co

    X *

    ROS

  • David Quig, PhD

    Further Metabolism of GS-conjugates

    GS-conjugates

    Cys(e) S-conjugate

    glutamate

    glycine

    GGT (inducible)

    dipepdidase

    Phase III

    Biol Pharm Bull(2001)24:1324-28

    Membrane bound

    N-acetyltransferase

    Mercapturic Acids Urine Bile Intestine

    *

    Phase III

  • David Quig, PhD

    Hepatic Detoxification Profile • D-glucaric acid- indicator of induction of CYP enzymes

    • Mercapturic acids- end products of GSH/Cys(e) conjugation

    • 48 yof, ill after starting work in brand new energy efficient office complex (VOC commonly about 10-X > outdoor air)

    First AM urine collection

  • David Quig, PhD

    Oxidative Stress and GSH Depletion

    Ox-LDL (apoB), endothelial dysfunction and, oxidized lipids, proteins and DNA (8-OH-dG)

    ↓ Cellular GSH

    Cd, As, Pb, Hg, / Fe, Cu, Co

    ROS ~ 4 million

    .OH/cell/day (1o mitochondria)

    Hg2+

    GSH

    GSH

    Am J Ind Med(2007)50:757-64 Alcohol Res Hlth(2003)27:277-84 Free Rad Biol Med(1995)18:321-36

  • David Quig, PhD

    Quenching Reactive Oxygen Species (radical /non-radical)

    • Superoxide Dismutases (Cu,Zn and Mn)

    SOD + 2 O2 . + 2 H+ → O2 + H2O2

    • GSH peroxidases - (selenium)

    2 H2O2 + 2 rGSH → GS-SG + 2 H2O

    (Also lipid peroxides → alcohols)

    • GSH reductase (inhibited by Pb, Hg, Cu, Cd)

    GS-SG + NADPH → 2 GSH (Mg and up to 10% of total body glucose “disposal”) Curr Vascular Pharmacol(2010)8:259-75 Curr Pharm Des(2009)15:2988-3002

    Biochim Biophys Acta(2009)1780:869-72 Arch Biochem Biophys(2009)485:56-62

  • David Quig, PhD

    Hair Elements- 48 yof, vegetarian

    Mg

    Zn

    Se

  • David Quig, PhD

    Serum Elements

    Mg

  • David Quig, PhD

    Whole Blood Elements

    Mg

    Zn

    Se

    As

  • David Quig, PhD

    Red Blood Cell Elements

    Se

    Mg

    Zn

    As

  • David Quig, PhD

    Phase III: Pump it Out! Membrane-bound efflux pumps- ↓ local cellular

    toxins (Phase II conjugates and their metabolites)

    • ENERGY DEPENDENT

    • MRPs- multidrug resistance-associated proteins Differential tissue distribution & substrate specificities

    • OATPs- organic anion-transport proteins

    Kidney proximal tubule membrane Hepatocyte canalicular membrane → bile → SI

    Pharmacogenomics(2008)9:105-27 Clin Exp Pham Physiol(2010)37:115-20 Biofactors(2003)17:103-14

  • David Quig, PhD

    Inflammation Compromises Detoxification • Inflammation of the intestines or liver compromises

    detoxification

    • Intestinal inflammation down-regulates hepatic efflux pump activity- suppression of basolateral secretion of toxins inhibits Phase II → increases oxidative stress

    • Determine the cause(s) of GI inflammation (CSAP)

    • Ameliorate inflammation- Optimize beneficial flora (↑butyrate), Vitamin D (dampens pro-inflammatory cytokines), curcumin and, ↑sIgA (S. boulardii, Lactobacillus GG, Bifidobacterium lactis Bb-12 )

    Toxicol Sci(2009)107:27-39 Am J Physiol(2007)292:G1114-22 JBC(2006)281:17883-89 Gut(2003)52:1788-95 Gastroenterol(2008)135:529-38 Immunity(2007)26:812-26

    J Appl Microbiol(2000)89:404-14

  • David Quig, PhD

    Essential Methionine (Met)

    • “Most important” essential amino acid (opinion!)

    • The start codon that initiates the synthesis every new molecule of DNA and RNA is the sequence for methionine.

    Met is required to start the synthesis of every protein.

    • Met is required for all methylation reactions and, all gene expression