Cobalt(I) Complex Nucleophile: Catalysis of Sn 2 Reactions with Alkyl Halides
Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted...
Transcript of Drug Metabolism 2 - MIT OpenCourseWare...Chemistry Unlike P450, Phase II reactions are concerted...
Drug Metabolism 2
Steven R. Tannenbaum 20.201
September 2013
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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
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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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Types of Conjugation Reactions
� Glucuronidations (UGTs) � Sulfations (STs) � Glutathione transferases (GSH, GST) � Methylations � Acetylations � Amino acid conjugations
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
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Glucuronidation Reaction
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Xenobiotics that are Glucuronidated
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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
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Sulfation Reaction
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Xenobiotics that are Sulfated
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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
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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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Glutathione Transferase Reaction
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Michael Reaction
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Important Points
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Cl
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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
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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
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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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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.
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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
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OHCH3 CH3CH3
CH3
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Prostaglandin H SynthaseCH3
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Metabolic interaction between the phenolic antioxidants, butylatedhydroxytoluene (BHT) and butylated hydroxya-nisole (BHA)
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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.
Note that the peroxyl radical can oxalic xenobiotics (X) in a peroxidative manner.
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Transcriptional regulation mediated by the Antioxidant Response Element
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