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40 Cards in this Set
- Front
- Back
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mj hub of metabolism
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ER microsomes (also cytoplasm, mito)
Liver |
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whole animal study of drug metabolism
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see how metabolites show up in blood and urine over time, but cannot determine tissue/protein binding.
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organ/cell study of drug metabolism
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cell specific eg brain...dunno if drug is in other cells and how being metabolized there...
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cell fractions study of drug metabolism
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identify enzs participating, but lose overall pic at animal, tissue, and cell level
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purified enzs study of drug metabolism
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enz-specific behavior at diff xeno concentrations
study reactive intermediates (expression of enz) |
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molecular biology study of drug metabolism
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probe mech of enz metabolism...why enz affected by metabolite?
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x-ray crystallography study of drug metabolism
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study 3d structure of active site to model what will happen w/ drug metabolites. computational chemistry
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factors that influence drug metabolism
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genetics
physiologic factors pharmacodynamic factors (incl noncovalent prot binding) environmental factors (eg induction) transporter proteins (influx/efflux of xeno) |
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bac biotransformation in GI
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1. bioactivation of drugs before absorption
2. enterohepatic circulation 3. biotransformation (deactivation/activation) |
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purine and pyrimidine oxidation enzyme
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xanthine oxidase
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monooxygenase O2 goes to:
H+ goes to |
substrate and h2o
help make h2o |
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liver microsomal electron transport
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NADPH*, NADH cofactors contributing e's
add NAD(P)H "enz" reductase to get your cytochrome P450 Monooxygenases! |
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isoform naming system
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CYP=general cytochrome p450
1=gene family (>40% same) A=subfamily (>55%) 1=individual family members |
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mj classes of CYP (genes for CYP450s are in italics)
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1a2
2c9 2d6 2e1 3a4 |
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CYP450 catalytic cycle
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iron 3+-->iron 2+ (from nadph via p450 reductase)-->iron 3+ ( from H+->h2o)
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catalytic intermediate of CYP450 catalytic cycle
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heme prosthetic group with "activated oxygen"
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intermediate between RH and ROH
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a one-electron process
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rxns catalyzed by CYP450:
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C-hydroxylation
Epoxidation N-, O-, & S-dealkylation N-Oxidation-primary and secondary desulfuration dehalogenation |
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FMO catalytic intermediate
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FADH2-OOH
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rxns catalyzed by FMO
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N-oxidation of secondary and tertiary amines
S-oxidation of thiols, disulfides, thioamides, thioureas, & thioethers |
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Prostaglandin H Synthase (COX)
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microsomal enz w/ 2 activities!
Need O2 & heme extrahepatic, not mj |
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activity 1 of prostaglandin H synthase
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fatty acid cyclooxygenase + O2 + heme (arachidonic acid-->(ROOH) PGG2)
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activity 2 of COX
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Prostaglandin hydroperoxidase
there is a co-oxidation of substrate (xeno)., the arachidonic acid is now in ROH PGH2 form |
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ROH PGH2 can be converted into...
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prostaglandins
thromboxane prostacyclin |
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rxns catalyzed by prostaglandin H synthase:
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aromatic C-hydroxylation
aromatic epoxidation one-electron oxidation of phenols, thiols, and arylamines |
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aromatic oxidation
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CYP, NADPH, H, O2
reactive epoxide intermediate that can undergo conjugation to GSH conjugate or hydrolysis before becoming the ROH. Accept PARA to any fxnl gps |
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aromatic oxidation rate determination
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e- withdrawing group decr rxn rate
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aliphatic hydroxylation
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CYP450
oxidize the first carbon off the benzene ring; otherwise usually last C |
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alkene oxidation
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leads to an epoxide & then various means of protecting from it (hydrolysis :), conjugation :), protein binding toxicity :( )
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Metabolic activation of quinones
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semiquinone radical
redox cycling CYP450 for NADPH Superoxide anion |
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O2 radical fate
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superoxide dismutase
catalase GSH peroxidase Fe+2 to hydroxide radical :( |
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hydrolytic rxns
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epoxide hydrolase and esterases
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alkene--> epoxide
epoxide hydrolase + water --> trans dihydrodiol |
esterase + water --> acid + alcohol
carboxyl and butyryl-cholinesterases as well as proteases for amide transesterification with alcohol and esterase |
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glucuronidation
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2NAD+/UDPG Dehydrogenase leads to Uridine-5'-diphospho-alpha-D-glucuronic acid (UDPGA)
Acceptor RZH/UGT alpha-D-Glc-1-Phosphate-->Beta glucuronide |
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UDPGA "not limiting"--acceptors must be
UGT/UDPGA |
cytosolic synthesis
microsomes (ER) for rxn |
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Z= (for glucuronidation)
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O, COO-, NG, or S
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Glucuronic acid acceptors
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Hydroxyl, carboxyl, amino, sulfur
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Sulfation
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SO4- is business end (PAPS) + ROH/Sulfotransferase (SULT) ---> ROSO3- + PAP
PAPS=2ATP + sulfur= limiting |
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Glucuronidation vs Sulfation: competition R-OH
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UDPGA not limiting
PAPS is limiting UGT-higher Km Sult-lower Km Glucuronidation: high capacity but low affinity (higher Km). Sulfation opposite. |
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Acetylation
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Deactivation
N-Acetyltransferase - |
