Biotransformation Xenobiotic metabolism - PowerPoint PPT Presentation

Loading...

PPT – Biotransformation Xenobiotic metabolism PowerPoint presentation | free to download - id: 40fcc6-YzhjM



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Biotransformation Xenobiotic metabolism

Description:

Where do biotransformations occur? Liver is the principal organ of drug metabolism although every tissue has some ability to metabolize drugs. – PowerPoint PPT presentation

Number of Views:422
Avg rating:3.0/5.0
Slides: 31
Provided by: mariab54
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Biotransformation Xenobiotic metabolism


1
Biotransformation Xenobiotic metabolism
  • Essentials of Toxicology

2
Biotransformation
  • Biotransformation means chemical alteration of
    chemicals such as nutrients, amino acids, toxins,
    xenobiotics or drugs in the body. It is also
    needed to render nonpolar compounds polar so that
    they are not reabsorbed in renal tubules and are
    excreted.
  • Biotransformation may results into-
  • Active Inactive form
  • Active Active or
    toxic form
  • Inactive Active form
  • Unexcretable Excretable form

3
Biotransformation
Results of biotransformation
Drug or Poison
biotransformed Drug or Poison
  • In general -
  • nonsynthetic precede synthetic reactions
  • nonsynthetic reactions can produce active
    metabolites
  • synthetic reactions produce inactive metabolites

4
Biotransformation
5
Biotransformation
Why is Biotransformation necessary? Most drugs
are excreted by the kidneys For renal
excretion drugs should have small molecular
mass be polar in nature should be fully
ionized at body pH Most drugs are complex and
do not have these properties and thus have to be
broken down to simpler products.
6
Biotransformation
Ctd
  • Pharmacologically active organic molecules tend
    to-
  • Be highly lipophilic remain unionized or
    partially ionized at physiologic PH.
  • Thus readily pass across biological barriers
    membranes
  • Strongly bound to plasma proteins
  • Such substances are not readily filtered at the
    glomerulus.
  • Their lipophilicity also facilitates to be
    reabsorbed through lipophilic renal tubular
    membranes.
  • This property also stops them from getting
    eliminated
  • They have to be converted to simpler
    hydrophilic compounds so that they are eliminated
    and their action is terminated.

7
Biotransformation
Ctd
Biotransformation can also result in
bioactivation, which involves the production of
reactive metabolites that are more toxic,
mutagenic, or carcinogenic than their parent
compound(s). Drugs may converted to- less
toxic materials more toxic materials
materials with different type of effect or
toxicity Beside these, biotransformation is
called a biochemical defense mechanism as it
handles different xenobiotics, drugs, toxicants,
body wastes (hemoglobin) or other unwanted
substances to those we get exposed.
8
Biotransformation
  • Where do biotransformations occur?
  • Liver is the principal organ of drug metabolism
    although every tissue has some ability to
    metabolize drugs.
  • Other tissues that display considerable activity
    include the GIT, the lungs, the skin, and the
    kidneys.
  • Following oral administration, many drugs (e.g.
    isoproterenol,morphine) absorbed intact from the
    small intestine and transported first via the
    portal system to the liver, where they undergo
    extensive metabolism ( first-pass metabolism).
  • Some orally administered drugs (e.g.clonazepam,
    chlorpromazine) are extensively metabolized in
    the intestine than in the liver.

9
Biotransformation
Ctd
  • Thus intestinal metabolism may contribute to the
    overall first-pass effect.
  • First pass effects may so greatly limit the
    bioavailability of orally administered drugs.
  • The lower gut harbors intestinal microorganisms
    that are capable of many biotransformation
    reactions.
  • Although drug biotransformation in vivo can occur
    by spontaneous, noncatalyzed chemical reactions,
    the vast majority are catalyzed by specific
    cellular enzymes.At the cellular level, these
    enzymes may be located in the
  • i) Endoplasmic reticulum ii) mitochondria iii)
    cytosol iii) lysosomes iv) even the nuclear
    envelope or v) plasma membrane.

10
Biotransformation
  • Water soluble xenobiotics are easier to eliminate
    in urine, feces but not exhalation as t1/2 is
    low.
  • Lipophilic barbiturates such as thiopental
    phenobarbital would have half-lives greater than
    100 years if they were not converted to
    water-soluble compounds.
  • Multiple enzymes (families)
  • Constitutively expressed
  • Inducible
  • Broad specificity
  • Polymorphic
  • Stereo-isomer specificity

11
Biotransformation
Relatively harmless
Potentially toxic xenobiotic
Metabolic activation
Detoxification
Inactive metabolite
Reactive intermediate
12
Converting lipophilic to water soluble compounds
Lipophilic (non-polar)
Xenobiotic
Phase I - Activation
Reactive intermediate
Phase II - Conjugation
Conjugate
Water soluble (polar)
Excretion
13
Phase I
  • introduction of functional group
  • hydrophilicity increases slightly
  • may inactivate or activate original compound
  • major player is CYP or mixed function oxygenase
    (MFO) system in conjunction with NAD(P)H
  • location of reactions is smooth endoplasmic
    reticulum

14
Phase II
  • conjugation with endogenous molecules
  • (GSH, glycine, cystein, glucuronic acid)
  • hydrophilicity increases substantially
  • neutralization of active metabolic intermediates
  • facilitation of elimination
  • location of reactions is cytoplasm

15
Phase I reactions
  • Oxidation
  • Hydroxylation (addition of -OH group)
  • N- and O- Dealkylation (removal of -CH side
    chains)
  • Deamination (removal of -NH side chains)
  • Epoxidation (formation of epoxides)
  • Oxygen addition (sulfoxidation, N-oxidation)
  • Hydrogen removal
  • Reduction
  • Hydrogen addition (unsaturated bonds to
    saturated)
  • Donor molecules include GSH, FAD, NAD(P)H
  • Oxygen removal
  • Hydrolysis
  • Splitting of C-N-C (amide) and C-O-C (ester) bonds

epoxide
16
Biotransformation
  • Activation of xenobiotics is a key element
  • (e.g. benzene, vinyl chloride)
  • Reactive intermediates include epoxides and free
    radical species (unpaired electrons) that are
    short-lived and hence highly reactive
  • Protection is provided by
  • endogenous antioxidant substances, e.g. GSH
  • vitamins C and E
  • antioxidant enzymes
  • Antioxidant molecules are oxidized in the process
    but have the capacity to regenerate the reduced
    form from the oxidized - NAD(P)H is a key player

17
Cytochrome P450 (CYP) Mixed Function Oxidases
(MFO)
  • Located in many tissues but highly in liver ER
  • Human 16 gene families
  • CYP 1,2,3 perform drug metabolism
  • gt48 genes sequenced
  • Key forms CYP1A2, CYP2C9, CYP2C19, CYP2D6,
    CYP2E1, and CYP3A4
  • Highly inducible
  • Alcohol CYP2E1
  • Barbiturates CYP2B

18
CYPs are the major enzymes involved in drug
metabolism, accounting for 75 of the total
metabolism.Most drugs undergo deactivation by
CYPs, either directly or by facilitated excretion
from the body. Also, many substances are
bioactivated by CYPs to form their active
compounds.
Proportion of drugs metabolized by different CYPs
19
Figure CYP450 Reaction Sequence
OH
NADPH H
e-
OH
CYP450 reductase
NADPH H

O
..
H
e-
O2
H2O
O21-
O2
20
Oxidation of vinyl chloride to an epoxide
21
Metabolic enzymes
  1. Microsomal
  2. CYP450 monooxygenases
  3. Flavin monooxygenase
  4. Non-microsomal
  5. Alcohol dehydrogenase
  6. Aldehyde dehydrogenase
  7. Monoamine and diamine oxidases
  8. Both
  9. Esterases and Amidases
  10. Prostaglandin synthase
  11. Peroxidases

22
Cooxidation of acetaminophen by prostaglandin
endoperoxide synthetase
23
Hydrolysis of esters and amides
24
Hydrolysis of organophosphates
25
(No Transcript)
26
(No Transcript)
27
(No Transcript)
28
Hydrolysis of epoxides
29
Stereoselective hydroxylation
30
Metabolism of benzo(a)pyrene to 9,10
epoxide Potent mutagen that binds DNA
About PowerShow.com