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42 Cards in this Set
- Front
- Back
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Xenobiotic
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Anything that is not normally in the body
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Order of sites of biotransformation
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Liver>>>>>intestinal mucosa, kidney, lung
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Phase I Type Rxns.
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Oxidation
Hydroxylation Reduction Hydrolysis |
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Phase 2 Type Rxns.
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Acetylation
Glucuronidation Sulfation A.A. Conjugation |
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Most common rxn in xenobiotic metabolism
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oxidation
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highest conc. of CYP450?
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liver
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Location of CYP450
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Smooth ER - 52
Mitochondria - 5 |
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Components of CYP450
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Fe-Protoporphoryn ring
Oxygen NADPH NADPH - CYP450 Reductase Phosphatidylcholine |
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Catalytic Pathway of CYP450
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Start Fe (Ferric)
Drug Binding Fe Reduction O2 Binding Oxygen Manipulation Drug oxidation and removal |
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Which CYP are most responsible isoforms to metabolize clinically relevant drugs?
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CYP3A & 2C
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Which CYP is important in the metabolism of environmental compounds?
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CYP1A2
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Top 3 largest metabolizers
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3A4/5 - 36%
2D6 - 21% 2C8/9 - 17% 2C18/19 - 8% |
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Properties of CYP1A1
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Aromatic Hydrocarbon Hydroxylase
Expressed in extrahepatic tissue (SI, skin, lung, placenta) Inducible Inter-individual variation |
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Properties of CYP1A2
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Environmental carcinogens
Liver, stomach, intestines Inducible Inter-individual variation |
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Properties of CYP2A6
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Liver, lung, nasal epithelium
Drugs (coumarin) & procarcinogens, nicotine Polymorphism |
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CYP2C
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CYP2C8 - liver & skin
CYP2C9 - primarily liver and intestine CYP2C19 - primarily liver and intestine 25% of clinically relevant drugs Polymorphisms |
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CYP2D6
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21% of clinically important drugs
not inducible Lipophilic Amines |
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CYP2E1
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small amount of drugs metabolized by this isoform
liver, kidney, intestine, lung inducible - alcohol, diet, diabetes polymorphism in Chinese *substrate is also inducer |
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CYP3A4
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Most abundant liver isoform (34%)
liver, intestine, lung, kidney, brain, uterus, placenta 1/3 of all clinically relevant drugs inducible inhibited by erythromycin activates aflatoxin b1 & benzo[a]pyrene *lipophilic drugs |
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Effects of induction
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Increased amount of CYP450 which increases activity which can decrease amount of drug in blood.
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Consequence of Self-Induction
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Alters pharmacokinetics & pharmacodynamics
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Examples of Inducers of CYP450
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Phenobarbital, rifampin
Cigarette Smoke Dietary Substances - sprouts, cabbage, cauliflower Alcohol |
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Effects of Rifampin & St. John's Wort
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Increase metabolism of OC
Decrease blood levels & effectiveness Increase metabolism of endogenous compounds Enhance activation of procarcinogens |
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Reversible Inhibition
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Fluoroquinolones
Cimetidine Antifungals Quinidine |
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Irreversible Inhibition
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Macrolide Antibiotics
Chloramphenicols Cyclophosphamide Spironolactones |
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SNPs
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Single nucleotide polymorphism substitutions
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Coding nonsynonymous
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change in nucleotide sequence with a change in a.a. composition
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Coding synonymous
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change in nucleotide sequence with no change in a.a. sequence
*1/2 life or transcription may be altered |
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Noncoding
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change in nucleotide sequence
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Indels
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Insertion/Deletions
short repeats or larger Indels gene deletion gene duplication |
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Polymorphic CYP
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CYP2A6
CYP2C9 CYP2C19 CYP2D6 |
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FMO
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Flavin containing mono-oxygenase
5 different isozymes Smooth ER Typically catalyzes oxygenation of N & S heteroatoms |
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Catalysis of Drug
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FAD --> Reduction --> Oxidation & Immediate Release --> Substrate oxidation
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MAO
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Monoamine oxidase
A - placenta only B - platelets & lymphocytes |
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Substrates of MAO
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primary, secondary & tertiary amines
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Location of MAO
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mitochondria
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Mechanism of MAO
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Drug + FAD --> oxidation
Drug + Water --> oxidation FADH2 + O2 --> FAD + peroxide |
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Inhibitors
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Non-specific --> phenelzin and tranylcypromine
MAO-A --> clorgyline MAO-B --> Pargyline & Selegiline |
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Properties of Alcoholic Dehydrogenase
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Zn containing
cytosolic 9 subunits NADH dependent Reversible |
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Substrates of Alcoholic Dehydrogenase
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primary and secondary alcohols
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Inihibitor of AD
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4-methylpyrazole
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Cause of flushing effect?
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ADH2*2 high activity in converting ETOH to acetaldehyde
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