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Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted...

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Drug Metabolism 2 Steven R. Tannenbaum 20.201 September 2013
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Page 1: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Drug Metabolism 2

Steven R. Tannenbaum 20.201

September 2013

Page 2: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Conjugation Reactions

� “Phase II” biotransformations attach a hydrophilic moiety onto drug/metabolite. The resulting product is too polar to re-cross membranes back into tissues and is readily excreted.

� These type of reactions most often abolish biological activity

Page 3: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Chemistry � Unlike P450, Phase II reactions are concerted reactions that

involve an electrophile (Y), a nucleophile (X) and a leaving group (L) � ��

� These reactions involve a pair of electrons, i.e., no radical intermediate

� Electron donating groups enhance nucleophilicity of substrate-favors reaction whereas, electron withdrawing groups decrease nucleophilicity-hinders reaction

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Page 4: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Types of Conjugation Reactions

� Glucuronidations (UGTs) � Sulfations (STs) � Glutathione transferases (GSH, GST) � Methylations � Acetylations � Amino acid conjugations

Page 5: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Uridine Diphosphoglucuronic Acid Transferases (UGT)

� UGTs are a family of enzymes, with two groups (UGT1A and UGT2B) � Found in same tissues as P450, microsomal � Uses uridine-5’-diphospho-�-D-glucuronic acid (UDPGA) as a cofactor � One of the most common conjugative reactions � Catalyze the glucuronidation of electron-rich nucleophilic

heteroatoms/sites � Alcohols (ROH) � Phenols (phenolic hydroxy groups, Ar-OH) � Carboxylic acids (R-COOH) � Aromatic Amines (Ar-NH2 or Ar-NHR) � Tertiary amines (R3-N) � Sulfhydryl groups (R-SH) � Carbons w/ sufficient nucleophilicity

Page 6: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Glucuronidation Reaction

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Page 7: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Xenobiotics that are Glucuronidated

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Page 8: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Sulfotransferases (ST) � STs are a family of enzymes with five members (SULT1-5,

SULT1 and 2 are most important in the metabolism of drugs � Found in liver, kidney, intestine, in cytosol � Catalyze the sulfation of

� Alcohols (R-OH) � Phenols (main group of substrates, Ar-OH) � Arylamines (Ar-NH2) � N-hydroxy compounds (R-NH-OH)

� Cofactor (3’-phosphoadenosine-5’-phosphosulfate, PAPS) is in limited supply, drug can overwhelm the system

� Low activity in some individuals thought to be the cause of wine induced headache

Page 9: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Sulfation Reaction

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Page 10: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Xenobiotics that are Sulfated

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Page 11: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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Degradationand

transportSynthesis

gly

cys

ProteinCoenzymefunctions

GSSGReductase

Oxidation reduction

GSH S-Conjugates

Protective functions

GSSG

GSH ThioltransferasesPeroxidases

Reactions withROS/RNS

GSH

NADP+

NADPH,H+

cys + glu

γ-glu-cys

Biological Roles and Cycle of Glutathione

Image by MIT OpenCourseWare.

Page 12: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Glutathione Transferases (GST)

� Family of enzymes (2 microsomal and 7 cytosolic)

� Referred to as an “electrophile killing” enzyme

� Uses reduced glutathione (GSH) as a cosubstrate ; Cysteine sulfhydryl group is the nucleophilic (attacking) moiety

� Glutathione can exist in a reduced form (GSH) or can be oxidized to a dimer (GSSG) via a disulfide bond

� GST catalyze the reaction of GSH with electrophiles � GSH is reactive on its own; the enzyme holds the substrate in place for an

increased reaction rate

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Page 13: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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Page 14: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Glutathione Transferase Reaction

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Page 15: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Michael Reaction

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Page 16: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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Important Points

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Page 17: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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Page 19: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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Cl

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CH3

Cl

Cl MO

O

M

MM

2,3,7,8-Tetrachlorodibenzo-p-dioxin Indolo(3,2-b)carbazole

3-Methylcholanthrene

Transformation

Benzo[a]pyrene

Structures of aromatic hydrocarbon (AH) receptor ligands. Examples of toxic halogenated aromatic hydrocarbons (2,3,7,8-Tetrachlorodibenzo-p-dioxin). Carcinogenic nonhalogenated polycyclic aromatic hydrocarbons (3-Methylc-holanthrene and Benzo[a]pyrene) and dietary constituents (Indolo(3,2-b)carbazole) are shown.

AHR

LigandHsp90Hsp90

Hsp90Hsp90

Hsp90Hsp90 AHRE

Nucleus

DME

Endobiotic and xenobiotic

merabolism

AAAAAA

AAA

mRNA

N Protein Cytoplasm

ARNT

AHR AHRARNT

AHRARNT

AHR = Aromatic Hydrocarbon ReceptorDME = Drug Metabolizing EnzymeAHRE = AH-responsive-elementARNT = AH-receptor-nuclear-translocatorHsp90 = Heat shok protein 90

Image by MIT OpenCourseWare.

Page 20: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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Selected human and rodent CYPs, UGTs and glucuronide transporters inducedby the Ah receptor. CAR and PXR.

Nuclear receptor

Uptake transporter

CYPs

AhR n.d. CYP1A1 UGT1A1 n.d.*

MRP2

MRP2MRP3

(mMrp2)

UGT1A6

UGT1A1

UGT1A1(mUgt1a6)(mUgt1a9)

(rUGT1A7)

(rUGT2B1)

CYP1A2

CYP2B6(rCYP2Bl)

(mCyp2b10)

CYP3A4(rCYP3A23)(mCyp3a11)

OATP2

OATP2

(mOatp2)

(mOatp2)PXR

CAR

UGTs Export transporter

Inducible rodent enzymes are listed in parenthesis.*n.d., not detected.

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Page 21: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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Page 39: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Page 40: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Page 41: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Page 42: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Page 43: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)
Page 44: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)
Page 45: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Page 46: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Source: Stepan, Antonia F., Daniel P. Walker, et al. "Structural �lert / �eactive �etabolite �oncept as �pplied in �edicinal��hemistry to �itigate the �isk of �diosyncratic �rug oxicity: � erspective �ased on the �ritical �xamination of rends�in the op 200 �rugs �arketed in the United States." ������������ ������������� 24, no. 9 (2011): 1345-410.

Published in: Antonia F. Stepan; Daniel P. Walker; Jonathan Bauman; David A. Price; Thomas A. Baillie; Amit S. Kalgutkar; Michael D. Aleo; Chem. Res. Toxicol. 2011, 24, 1345-1410. Copyright © 2011 American Chemical Society

Page 47: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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Page 49: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

Page 50: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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Page 52: Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted reactions that involve an electrophile (Y), a nucleophile (X) and a leaving group (L)

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T Lymphocyte

ActivatedT Lymphocyte

Cytokines(e.g., IL-12)

ActivatedMacrophage

TNF,IL-1

TNFPresents

Antigen toT cells

OtherInflammatory

Mediators

OtherInflammatory

Mediators

Inflammation InflammationMacrophage

IFN-γ

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Overview of liver zonal analysis

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OHCH3 CH3CH3

CH3

Phenoxy radical

O+

OCH3 OCH3

BHA2H+.2e-

Prostaglandin H SynthaseCH3

CH2

CH3

CH3

CH3

CH3CH3 CH3

CH3

CH3

CH3

CH3

CH3

CH3O

O+ CH3

CH3 CH3 CH3

CH3

CH3

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OHCH3

CH2

Quinone methide

Phenoxyl radical

Cytochrome P450

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BHT

x2 x2

Metabolic interaction between the phenolic antioxidants, butylatedhydroxytoluene (BHT) and butylated hydroxya-nisole (BHA)

N

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C4H3

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Carbon-centeredradical

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Phenylbutazone(anionic form of

the enol tautomer)

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O

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O

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Oxidation of phenylbutazone by prostaglandin H synthase (PHS) to acarbon-centered radical and peroxyl radical.

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Note that activation of BHT to a toxic quinone methide can be catalyzed bycytochrome P450 or. In the presence of BHA, by prostaglandin H synthase.

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Transcriptional regulation mediated by the Antioxidant Response Element

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20.201 Mechanisms of Drug ActionsFall 2013

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