Metabolism of Xenobiotics - PowerPoint PPT Presentation

1 / 39
About This Presentation
Title:

Metabolism of Xenobiotics

Description:

ENVR/TOXC 442 Fall 2012 Metabolism of Xenobiotics II. Phase 1 Metabolism Aug 23, 2012 L.M. Ball Rosenau 158 lmball_at_unc.edu Monoamine oxidase Metabolizes endogenous ... – PowerPoint PPT presentation

Number of Views:396
Avg rating:3.0/5.0
Slides: 40
Provided by: BALL170
Category:

less

Transcript and Presenter's Notes

Title: Metabolism of Xenobiotics


1
Metabolism of Xenobiotics
ENVR/TOXC 442 Fall 2012
  • II. Phase 1 Metabolism
  • Aug 23, 2012
  • L.M. Ball
  • Rosenau 158
  • lmball_at_unc.edu

2
Phase I reactions
  • Chemical modification of xenobiotics
  • Introduces or uncovers polar functional groups
    that provide sites for Phase II metabolism
  • Major classes of reaction
  • Oxidation
  • Reduction
  • Hydrolysis

3
Overview of oxidations, reductions, hydrolyses
  • Oxidation
  • Loss of electrons M M e-
  • Gain of oxygen R O RO

4
Oxidation reactions
Hydroxylation
5
Epoxidation
6
Demethylation
Deethylation
7
Overview of oxidations, reductions, hydrolyses
  • Reduction
  • Gain of electrons M e- M
  • Loss of oxygen RO R O
  • Gain of hydrogen R H RH

8
Reduction
  • Nitro to amino group
  • Chromium VI to Chromium III

Cr6 3 e- Cr3
9
Hydrolysis
  • Addition of water
  • Cleavage of R-O or R-N bond accompanied by
    addition of H2O
  • R-O-R H2O R-O-H R-OH
  • R-N-R H2O R-N-H R-OH
  • H H

10
Principal Phase I enzymes
  • Cytochrome P450
  • Flavin monooxygenase
  • Monoamine oxidase
  • Esterases
  • Amidases
  • Hydrolases
  • Reductases, dehydrogenases, oxidases

11
Cytochrome P450
  • Heme protein
  • Terminal oxidase of the mixed-function oxidase
    (MFO) electron-transfer system
  • Located in the smooth endoplasmic reticulum of
    all major organs and tissues
  • Uses NADPH as a source of reducing equivalents
  • Inducible

12
Cytochrome P450
  • Heme protein
  • Terminal oxidase of the mixed-function oxidase
    (MFO) electron-transfer system
  • Located in the smooth endoplasmic reticulum of
    all major organs and tissues
  • Uses NADPH as a source of reducing equivalents
  • Inducible

13
Overall reaction
R-H O2 NADPH H R-OH H2O NADP
14
(No Transcript)
15
Ferric protoporphyrin IX
16
Protoporphyrin IX
17
Catalytic cycle of cytochrome P450
ROH
H
Fe3
RH
HO22- Fe3-RH
H2O
Fe3-RH
from NADPH-cytC reductase
e-
H2O2
H
HO2- Fe2-RH
Fe2-RH
O2 Fe2-RH
O2
O2-.
H e-
18
(No Transcript)
19
P450 and reductase in endoplasmic reticulum
20
The P450 gene superfamily
  • Format of nomenclature
  • CYPFamily/Subfamily/Gene
  • Family 1, 2, 150 and counting
  • 40 aa similarity
  • Subfamily A, B,HW
  • 55-65 aa similarity
  • Gene 1, 2..10 or above
  • gt97 aa similarity (allelic variants)
  • Families grouped in Clans

21
Sub- Family family Gene
CYP1 A 1 BaP hydroxylation,
O-deethyln (PAC-inducible 2 N-hydroxylation,
O-deethylation CYP2 A 1 Testosterone
7?-hydroxylation 2 Testosterone
15?-hydroxylation B 1 Aliphatic
hydroxylation 2 O-deethylation C 1 -
20 2C19, mephenytoin hydroxylase
22
Demethylation
Deethylation
23
Sub- Family family Gene
CYP1 A 1 BaP hydroxylation,
O-deethyln (PAC-inducible 2 N-hydroxylation,
O-deethylation CYP2 A 1 Testosterone
7?-hydroxylation 2 Testosterone
15?-hydroxylation B 1 Aliphatic
hydroxylation 2 O-deethylation C 1 -
20 2C19, mephenytoin hydroxylase
24
(No Transcript)
25
Sub- Family family Gene
CYP2 D 1 - 6 2D6, debrisoquine
hydroxylase E 1 C- and N-hydroxylation
small molecules 2 F 1 CYP3
A 1-4 3A4 CYP4 A 1 Lauric acid ?-
and ?-1 hydroxylation
26
Polymorphisms
27
Sub- Family family Gene
CYP11 (mito) A 1 Steroid 11?-hydroxylation CYP1
7 A 1 Steroid 17?-hydroxylation CYP21
A 1 Steroid 21-hydroxylation CYP51 A 1
(Plants, yeast) CYP52-66 A Yeasts,
fungi CYP71-99, 701 Plants CYP101 A 1
Pseudomonas putida P450cam CYP102-132
A Bacteria
28
(No Transcript)
29
Contributions of enzymes to the metabolism of
Pfizer-marketed drugs. Guengerich, 2008.
30
Changes in P450 levels with ageRats
M 2C6, 2C11, 3A2 F 2A1, 2C6, 2C12
2A1 2C6 3A2
31
  • Protein data bank 101
  • Human P450 nomenclature
  • Human P450s substrates, inhibitors, inducers
  • Human CYP1A1 in Protein Knowledgebase

32
Flavin monooxygenase
  • Flavoprotein
  • Mixed-function amine oxidase
  • Located in smooth endoplasmic reticulum, in
    human, pig, rabbit liver, guinea-pig lung, human
    kidney
  • Uses NADPH as a source of reducing equivalents
  • Not inducible

33
Overall reaction
R-H O2 NADPH H R-OH H2O NADP
34
Monoamine oxidase
  • Metabolizes endogenous monoamine
    neurotransmitters
  • Uses NADPH as a source of reducing equivalents
  • Found in the endoplasmic reticulum and in
    mitochondria, of nerve endings and liver

35
Esterases
  • Hydrolyse esters to carboxylic acid and alcohol
    functional groups
  • Non-specific esterases in plasma, more
    substrate-specific forms in liver cytosol

36
Amidases
  • Hydrolyse amides to carboxylic acids and amines
    (or ammonia)
  • Found in plasma and in liver cytosol

37
Hydrolases
  • Hydrolyse ethers

38
Reductases, dehydrogenases, oxidases
  • In cytosol, endoplasmic reticulum, mitochondria

39
Outcomes
  • Slight gain in water solubility (ionizable
    hydroxyl, amino groups)
  • Sites for Phase 2 reactions attachment of
    glucuronyl, sulfate, glutathione residues gt major
    gain in water-solubility.
  • Formation of reactive electrophiles e.g. epoxides
    (especially polycyclic aromatic hydrocarbons)
  • Formation of sites for redox cycling (catechols
    lt-gtquinones) gt ROS
Write a Comment
User Comments (0)
About PowerShow.com