metabolism of xenobiotics
Download
Skip this Video
Download Presentation
Metabolism of Xenobiotics

Loading in 2 Seconds...

play fullscreen
1 / 39

Metabolism of Xenobiotics - PowerPoint PPT Presentation


  • 86 Views
  • Uploaded on

ENVR/TOXC 442 Fall 2012. Metabolism of Xenobiotics. II. Phase 1 Metabolism Aug 23, 2012 L.M. Ball Rosenau 158 [email protected] Phase I reactions. Chemical modification of xenobiotics Introduces or uncovers polar functional groups that provide sites for Phase II metabolism

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Metabolism of Xenobiotics' - mali


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
metabolism of xenobiotics
ENVR/TOXC 442 Fall 2012

Metabolism of Xenobiotics

II. Phase 1 Metabolism

Aug 23, 2012

L.M. Ball

Rosenau 158

[email protected]

phase i reactions
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
overview of oxidations reductions hydrolyses
Overview of oxidations, reductions, hydrolyses
  • Oxidation
    • Loss of electrons M M+ + e-
    • Gain of oxygen R + O RO
oxidation reactions
Oxidation reactions

Hydroxylation

slide6
Demethylation

Deethylation

overview of oxidations reductions hydrolyses1
Overview of oxidations, reductions, hydrolyses
  • Reduction
    • Gain of electrons M+ + e- M
    • Loss of oxygen RO R + O
    • Gain of hydrogen R + H RH
reduction
Reduction
  • Nitro to amino group
  • Chromium VI to Chromium III

Cr6+ + 3 e- Cr3+

hydrolysis
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

principal phase i enzymes
Principal Phase I enzymes
  • Cytochrome P450
  • Flavin monooxygenase
  • Monoamine oxidase
  • Esterases
  • Amidases
  • Hydrolases
  • Reductases, dehydrogenases, oxidases
cytochrome p450
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
cytochrome p4501
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
overall reaction
Overall reaction

R-H + O2 + NADPH + H+

R-OH + H2O + NADP+

catalytic cycle of cytochrome p450
NADH

NADPH

Catalytic cycle of cytochrome P450

ROH

H+

Fe3+

+ RH

HO22-

Fe3+-RH

H2O

Fe3+-RH

+ e-

from NADPH-cytC reductase

H2O2

H+

HO2-

[Fe2+-RH]

Fe2+-RH

O2

[Fe2+-RH]

+O2

O2-.

H+ + e-

the p450 gene superfamily
The P450 gene superfamily
  • Format of nomenclature:

CYPFamily/Subfamily/Gene

  • Family = 1, 2, …150 and counting
    • ~40% aa similarity
  • Subfamily = A, B,…H…W
    • 55-65% aa similarity
  • Gene = 1, 2..10 or above
    • >97% aa similarity (allelic variants)
  • Families grouped in Clans
sub family family gene
Sub- Family family Gene

CYP1 A 1 BaP hydroxylation, O-deethyl’n

(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

slide22
Demethylation

Deethylation

sub family family gene1
Sub- Family family Gene

CYP1 A 1 BaP hydroxylation, O-deethyl’n

(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

sub family family gene2
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

sub family family gene3
Sub- Family family Gene

CYP11 (mito) A 1 Steroid 11-hydroxylation

CYP17 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

slide29
Contributions of enzymes to the metabolism of Pfizer-marketed drugs.

Guengerich, 2008.

changes in p450 levels with age rats
Changes in P450 levels with ageRats

M: 2C6, 2C11, 3A2

F: 2A1, 2C6, 2C12

2A1

2C6

3A2

slide31
Protein data bank 101
  • Human P450 nomenclature
  • Human P450s: substrates, inhibitors, inducers
  • Human CYP1A1 in Protein Knowledgebase
flavin monooxygenase
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

overall reaction1
Overall reaction

R-H + O2 + NADPH + H+

R-OH + H2O + NADP+

monoamine oxidase
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

esterases
Esterases

Hydrolyse esters to carboxylic acid and alcohol functional groups

Non-specific esterases in plasma, more substrate-specific forms in liver cytosol

amidases
Amidases

Hydrolyse amides to carboxylic acids and amines (or ammonia)

Found in plasma and in liver cytosol

hydrolases
Hydrolases

Hydrolyse ethers

reductases dehydrogenases oxidases
Reductases, dehydrogenases, oxidases

In cytosol, endoplasmic reticulum, mitochondria

outcomes
Outcomes
  • Slight gain in water solubility (ionizable hydroxyl, amino groups)
  • Sites for Phase 2 reactions – attachment of glucuronyl, sulfate, glutathione residues > major gain in water-solubility.
  • Formation of reactive electrophiles e.g. epoxides (especially polycyclic aromatic hydrocarbons)
  • Formation of sites for redox cycling (catechols <->quinones) > ROS
ad