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    Metabolism of Xenobiotics

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    Czarina Rivera
    1. Xenobiotics undergo two phase metabolism in the body, particularly the liver, to make them more hydrophilic and able to be excreted. Phase 1 involves reactions like oxidation while phase 2 involves conjugation. 2. Cytochrome P450 enzymes play a key role in phase 1 as monooxygenases, adding new functional groups through reactions like hydroxylation. 3. Conjugation in phase 2 involves adding groups like glucuronic acid, sulfate, or glutathione to make the xenobiotic more hydrophilic through reactions catalyzed by transferase enzymes. 4. Metabolism can activate or deactivate xenobiotics and influence their effects, with genetic and other factors impacting

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    Metabolism of Xenobiotics

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    Czarina Rivera
    267 views30 pages
    1. Xenobiotics undergo two phase metabolism in the body, particularly the liver, to make them more hydrophilic and able to be excreted. Phase 1 involves reactions like oxidation while phase 2 involves conjugation. 2. Cytochrome P450 enzymes play a key role in phase 1 as monooxygenases, adding new functional groups through reactions like hydroxylation. 3. Conjugation in phase 2 involves adding groups like glucuronic acid, sulfate, or glutathione to make the xenobiotic more hydrophilic through reactions catalyzed by transferase enzymes. 4. Metabolism can activate or deactivate xenobiotics and influence their effects, with genetic and other factors impacting

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    METABOLISM OF XENOBIOTICS

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    METABOLISM OF XENOBIOTICS

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    1. Xenobiotics undergo two phase metabolism in the body, particularly the liver, to make them more hydrophilic and able to be excreted. Phase 1 involves reactions like oxidation while phase 2 involves conjugation. 2. Cytochrome P450 enzymes play a key role in phase 1 as monooxygenases, adding new functional groups through reactions like hydroxylation. 3. Conjugation in phase 2 involves adding groups like glucuronic acid, sulfate, or glutathione to make the xenobiotic more hydrophilic through reactions catalyzed by transferase enzymes. 4. Metabolism can activate or deactivate xenobiotics and influence their effects, with genetic and other factors impacting

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    267 views30 pages

    Metabolism of Xenobiotics

    Uploaded by

    Czarina Rivera
    1. Xenobiotics undergo two phase metabolism in the body, particularly the liver, to make them more hydrophilic and able to be excreted. Phase 1 involves reactions like oxidation while phase 2 involves conjugation. 2. Cytochrome P450 enzymes play a key role in phase 1 as monooxygenases, adding new functional groups through reactions like hydroxylation. 3. Conjugation in phase 2 involves adding groups like glucuronic acid, sulfate, or glutathione to make the xenobiotic more hydrophilic through reactions catalyzed by transferase enzymes. 4. Metabolism can activate or deactivate xenobiotics and influence their effects, with genetic and other factors impacting

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    of 30

    METABOLISM OF XENOBIOTICS

    Raymond Oliver A. Cruz, MD raymondolivercruz.wordpress.com

    WHAT IS A XENOBIOTIC?
    A xenobiotic is a compound that is foreign to the body It may include drugs, chemical carcinogens, and various other compounds The xenobiotic may be excreted unchanged, or it may me metabolized by the bodys enzymes to other compounds

    Metabolism of Xenobiotics
    Occurs in mostly in liver (enzymatic processes)
    Convertion into more hydrophilic substances - excretion via urine May convert procarcinogenics into cytotoxic, mutagenic compounds Different persons may have differences in metabolism (genetic diff., physiol. factors)

    Metabolism of one xenobiotic may influence metabolism of another


    Xenobiotics Drugs Other foreign non-essential compounds Metabolism in non-hepatic tissue Intestinal mucosa Kidney Lung Bacteria in GI-tract

    First-pass metabolism: Xenobiotic metabolized before reaching general circulation

    2 PHASES OF XENOBIOTIC METABOLISM


    1. Hydroxylation / Biotransformation 2. Conjugation

    Pathways of metabolism Phase 1: Biotransformation Attachment of new functional groups, transformation of existing func. grps, oxidation, reduction, hydroxylation, hydrolysis etc. Phase 2: Conjugation. Masking of an existing functional group by acetylation, glycosylation, attachment of an amino acid, or other mechanism

    More hydrophilic drug

    Renal excretion
    CH3

    NH

    NH

    Demethylation
    HO O OH

    Conjugation glucuronic acid


    HO O OH

    Phase 1

    Phase 2

    HO

    HO

    OH O OH CO2H

    Morphine

    HYDROXYLATION
    Catalyzed by cytochrome P450, a monooxygenase Hydroxylation may sometimes terminate the action of a drug Other phase 1 reactions may include deamination, dehalogenation, desulfuration, epoxidation, peroxygenation, and reduction Reactions involving hydrolysis also occur in phase 1

    CYTOCHROME P 450
    The reaction catalyzed by a monooxygenase is as follows: RH + O2 +NADPH + H+ R-OH + H2O + NADP It is sometimes referred to as a Mixed Function Oxidase Approximately 50% of the drugs humans ingest are metabolized by isoforms of cytochrome P450

    Participation of the CYP Enzymes in Metabolism of Some Clinically Important Drugs


    CYP Enzyme Examples of substrates
    1A1
    1A2 2A6

    Caffeine, Testosterone, R-Warfarin


    Acetaminophen, Caffeine, Phenacetin, R-Warfarin 17-Estradiol, Testosterone

    2B6
    2C-family

    Cyclophosphamide, Erythromycin, Testosterone


    Acetaminophen, Tolbutamide (2C9); Hexobarbital, SWarfarin (2C9,19); Phenytoin, Testosterone, R- Warfarin, Zidovudine (2C8,9,19);

    2E1
    2D6 3A4

    Acetaminophen, Caffeine, Chlorzoxazone, Halothane


    Acetaminophen, Codeine, Debrisoquine Acetaminophen, Caffeine, Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and RWarfarin, Phenytoin, Testosterone, Halothane, Zidovudine

    Adapted from: S. Rendic Drug Metab Rev 34: 83-448, 2002

    CONJUGATION
    Compounds produced in phase 1 are converted by specific enzymes to various polar metabolites by conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation

    GLUCURONIDATION
    UDP-glucuronic acid is the glucuronyl donor, and glucuronosyltransferases are the catalysts This is the most frequent conjugation reaction

    SULFATION
    Sulfate donor is adenosine 3-phosphate5-phosphosulfate (PAPS), called active sulfate.

    GLUTATHIONE
    Glutathione (-glutamyl-cysteinylglycine) is a tripeptide consisting of glutamic acid, cysteine, and glycine Electrophilic xenobiotics (such as certain carcinogens) are conjugated to the nucleophilic GSH: R+GSHRSG The enzymes catalyzing these reactions are called glutathione S-transferases and are present in high amounts in liver cytosol

    ACETYLATION
    X+Acetyl-CoAAcetyl-X + CoA Catalyzed by acetyltransferases present in the cytosol of various tissues, particularly the liver The drug isoniazid, used in the treatment of tuberculosis, is subject to acetylation

    ACETYLATION
    Polymorphic types of acetyltransferases exist, resulting in individuals who are classified as slow or fast acetylators Slow acetylators are more subject to certain toxic effects of isoniazid because the drug persists longer in these individuals

    METHYLATION

    Conjugation Reactions Glucuronidation


    CO2H O OH HO O OH O P O P O CH2 OH O OH ON O NH O

    + ROH or R 3N UGT

    CO2H OO R OH OH OH

    O-glucuronide
    CO2H R + N R O R OH OH OH

    UDP- -D-glucuronic acid

    N+-glucuronide

    Liver has several soluble UDP-Gluc-transferases

    HO 3 N O N CH3
    6

    N N

    CH3

    HO

    Morphine

    Am itriptyline

    Cotinine

    Glucuronic acid conjugation to phenols, 3-amines, aromatic amines

    Conjugation Reactions Sulfation


    R OH
    NH2 N N

    +
    N N H O H OH O OH O P O S O O

    O R O S OH O

    (PAPS, 3-phosphoadenosine5-phosphosulfate)

    H HO

    H OH

    Examples: ethanol, p-hydroxyacetanilide, 3-hydroxycoumarin

    H2N N O

    H2N O HO S O N

    NH2

    NH

    Minoxidil

    Minoxidil-sulfate

    Sulfation may produce active metabolite

    Conjugation Reactions Acetylation

    O Ar NH2 CoA S O Ar N H R N H CH3 CH3 O R S R O R NH2 R OH R SH

    O CH3 O CH3

    Acetyl transferase

    Examples: Procainamide, isoniazid, sulfanilimide, histamine


    NAT enzyme is found in many tissues, including liver

    PURPOSE OF XENOBIOTIC METABOLISM


    To increase the water solubility of the xenobiotic and facilitate excretion from the body If xenobiotic is not metabolized, it would remain in the nonpolar state and would be stored indefinitely in the adipose tissues

    A METABOLIZED XENOBIOTIC MAY HAVE THE FOLLOWING FATES:


    It may be converted from an inactive to a biologically active compound (prodrug or procarcinogen) Additional phase 1 reactions may convert the active compounds to less active or inactive forms prior to conjugation.

    A METABOLIZED XENOBIOTIC MAY HAVE THE FOLLOWING FATES:


    In other cases, it is the conjugation reactions that convert the active products of phase 1 reactions to less active or inactive species, which are subsequently excreted in the urine or bile In a very a few cases, conjugation may increase the biologic activity of a xenobiotic

    PROPERTIES OF HUMAN CYTOCHROME P450


    All are hemoproteins Exhibit broad substrate specificity Found mostly in the liver but is also present in other tissues A mitochondrial or endoplasmic reticulum enzyme Activity may be induced or depressed by certain drugs, causing drug interactions

    Ex. Warfarin, used to prevent blood clotting, is metabolized by a cytochrome which is induced by Phenobarbital. Thus when both drugs are given, warfarin dose must be increased to achieve therapeutic doses.

    PROPERTIES OF HUMAN CYTOCHROME P 450


    Exhibits genetic polymorphism, so different individuals metabolize drugs differently Activity is affected also by tissue or organ disease (e.g. Cirrhosis) NADPH, not NADH, is involved in the reaction mechanism The preferred lipid in its structure is phosphatidylcholine

    CYTOCHROME NOMENCLATURE
    CYP cytochrome Arabic number family (40% or more sequence identity) Capital letter subfamily (>55% sequence identity) Individual P450s are given arabic numerals Ex. CYP1A1 means it is a member of family 1 subfamily A and is the first individual member of the subfamily

    RESPONSE TO XENOBIOTICS
    May be affected by age, sex, and genetic factors (Pharmacogenomics) Reaction to drugs: Pharmacogenetics May result in cell injury, allergies, or carcinogenesis

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