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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

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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



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


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


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

Guengerich, 2008.


Changes in p450 levels with age rats
Changes in P450 levels with age Pfizer-marketed drugs.Rats

M: 2C6, 2C11, 3A2

F: 2A1, 2C6, 2C12

2A1

2C6

3A2


  • Protein data bank 101 Pfizer-marketed drugs.

  • Human P450 nomenclature

  • Human P450s: substrates, inhibitors, inducers

  • Human CYP1A1 in Protein Knowledgebase


Flavin monooxygenase
Flavin monooxygenase Pfizer-marketed drugs.

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 Pfizer-marketed drugs.

R-H + O2 + NADPH + H+

R-OH + H2O + NADP+


Monoamine oxidase
Monoamine oxidase Pfizer-marketed drugs.

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 Pfizer-marketed drugs.

Hydrolyse esters to carboxylic acid and alcohol functional groups

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


Amidases
Amidases Pfizer-marketed drugs.

Hydrolyse amides to carboxylic acids and amines (or ammonia)

Found in plasma and in liver cytosol


Hydrolases
Hydrolases Pfizer-marketed drugs.

Hydrolyse ethers


Reductases dehydrogenases oxidases
Reductases, dehydrogenases, oxidases Pfizer-marketed drugs.

In cytosol, endoplasmic reticulum, mitochondria


Outcomes
Outcomes Pfizer-marketed drugs.

  • 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


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