Term
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Definition
the chemical alteration of xenobiotics within the body.
This may involve rearrangement of chemical bonds, incorporation or loss of atoms or molecules, or some combination. |
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Term
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Definition
| any compound normally foreign to living systems |
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Term
| What 3 things can cause xenobiotic biotransformation? |
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Definition
Enzymatic processes
Non-enzymatic processes
Rearrangements |
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Term
| What usually metabolizes drugs and/or xenobiotics that are analogues of physiological substances? |
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Definition
| Specific enzymes normally responsibile for the disposition of these compounds. |
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Term
| What can metabolize drugs and/or xenobiotics that have no edogenous counterparts? |
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Definition
| Enzyme systems that exhibit broad substrate specificity |
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Term
| What are the 3 reasons drug biotransformation is necessary? |
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Definition
1) Highly polar drugs are generally poorly absorbed & poorly transported across membranes.
2) Metabolism results in the transformation to more polar, hydrophilic compounds more readily excreted
3) Metabolic transformation facilitates elmination and may result in inactivation |
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Term
| What is the principal organ of drug metabolism (tho nearly all tissues have some capacity)? |
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Definition
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Term
| What 4 "portals of entry" have significant capacity for drug metabolism? |
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Definition
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Term
| How much capacity for xenobiotic metabolism do the kidneys have? |
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Definition
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Term
| What 3 things contribute to the first pass effect restricting bioavailability of some oral drugs? |
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Definition
1) Oral drugs absorbed from sm. intestine are transported to the liver via the portal system and extensively metabolized prior to systemic circulation.
2) With some drugs, extensive metabolism also occurs in the intestinal mucosa
3) To a lesser extent, microorganisms can also metabolize drugs and contribute to the first pass effect. |
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Term
| What are the 3 subcellular localizations of drug-metabolizing enzymes? |
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Definition
1) smooth ER
2) cytoplasm
3) mitochondria |
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Term
| What occurs in Phase I metabolism? |
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Definition
| Oxidation, Reduction, Hydrolysis => metabolite becomes more polar and possibily more readily excreted or ready for additional metabolism. |
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Term
| What occurs in Phase II metabolism? |
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Definition
| Conjugation of sm., endogenous substrate with functional groups already present on the drug or with those that are added/revealed by Phase I metabolism. |
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Term
| What 2 compartments are P450s found in? |
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Definition
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Term
| Are P450s usually Phase I or Phase II metabolism enzymes? |
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Definition
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Term
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Definition
| a system where a flavoprotein is coupled to a hemoprotein terminal oxidase |
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Term
| What is the flavoprotein in the CYP450 system? |
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Definition
| NADPH CYP450 oxidoreductase |
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Term
| What is the hemoprotein terminal oxidase in the CYP450 system? |
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Definition
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Term
| What does the CYP450 system require as a source of reducing equivalents? |
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Definition
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Term
| What type of environment is the CYP450 system in? |
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Definition
| lipid environment. (therefore a membrane protein) |
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Term
| How is CYP450 identified? |
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Definition
| Distinct optical spectrum, due to thiol ligan to heme moiety |
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Term
| How many genes, gene families, & subfamilies are there of CYP450? |
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Definition
>600 genes
18 human gene families
44 subfamilies |
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Term
CYP450 Catalytic Cycle
[image] |
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Definition
1) e-
2) O2
3) e-
4) H2O
5) [image] |
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Term
| What is the nomenclature system regarding CYP450? |
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Definition
CYP#Letter#
CYP - CYP450
1st # - Gene Family
Letter - Gene Subfamily
2nd # - Individual Gene |
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Term
| What is the nomenclature for a P450 pasudogene? |
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Definition
| P450 name followed by a P |
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Term
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Definition
| defective gene that doesn't produce a functional protein. |
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Term
| How are psaudogenes formed? |
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Definition
| As relics of gene duplications where one of the copies has degenerated and lost its function. |
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Term
| Why are CYP450s capable of catalyzing a wide variety of monooxygenase reactions? |
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Definition
| broad substrate specificity as individual proteins & as a super-family of enzymes. |
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Term
| What are the 7 reactions cyp450 can do? |
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Definition
1) Dealkylation & Deamination
2) Dehalogenation
3) Desulfuration
4) Epoxidation
5) Hydroxylation
6) N-oxidation
7) Sulfur oxidation |
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Term
| What 2 types of molecules can P450 hydroxylate? |
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Definition
Aliphatic (non-aromatic cyclic or acyclic)
Aromatic |
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Term
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Definition
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Term
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Definition
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Term
def
dealkylation and deamination |
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Definition
| removal of an HX group or an amino group (-NH2), where X is OR, NR2, SR |
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Term
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Definition
| A) Hydroxylamines
R2NH -> R2N-OH
B) N-oxides
R2N -> R2N-O |
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Term
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Definition
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Term
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Definition
RX -> ROH
X = F, Cl, Br, I, At, Uus |
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Term
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Definition
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Term
| Which CYP familes are involved in drug metabolism? |
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Definition
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Term
| Which CYP450 is involved in the biotransformation of almost all drugs? (also significant to poor bioavialability of drugs) |
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Definition
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Term
| What metabolism are the other CYP450 families important for? |
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Definition
| Endogenous compunds s.a. setroids & FA |
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Term
| What additional proteins are needed by Flavin-Containing monooxygenases (FMOs)? |
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Definition
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Term
| What monooxygenase reactions do FMOs catalyze? |
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Definition
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Term
| What do FMOs require that CYP450s also require? |
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Definition
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Term
| Where are FMOs localized in the cell? |
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Definition
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Term
| What do FMOs prefer to oxidize over hydroxyl amines & N-oxides? |
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Definition
| oxidation of secondary & tertiary amines & S-oxidation |
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Term
| How many FMO gene products are there in mammals? |
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Definition
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Term
| How are CYP450s & FMOs similar? |
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Definition
1) ER localization
2) require NADPH
3) same overall rxn
4) broad substrate specificity
5) multigene family |
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Term
| How are CYP450s & FMOs different? |
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Definition
1) P450s are also in mitochondria
2) FMOs have no accessory protein
3) FMOs prefer oxidation of secondary & tertiary amines vs. primary amines
4) FMO catalyzes S-oxidation
5) FMOs have of 5 genes while P450 has >600
6) Catalytic cycle differences in order |
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Term
| What can FMOs do to thiols? |
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Definition
| form a S-S bridge to connect them |
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Term
| What does FMO do to tertiary amines? |
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Definition
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Term
| What does FMO do to hydrazines? |
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Definition
| forms 2 ractive intermediates |
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Term
| What does FMO do to sulfides? |
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Definition
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Term
FMO Catalytic Cycle
[image] |
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Definition
| 1) NADPH + H+
2) O2
3) OX (X is the xenobiotic substrate)
4) NADP+ + H2O |
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Term
| What do the Phase II metabolism conjugation reactions involve? |
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Definition
| High-energy intermediates & transferases |
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Term
| How many steps are there to the glucuronidation pathway? |
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Definition
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Term
| What occurs in setps 1 & 2 in the glucuronidation pathway? |
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Definition
| glucose activation/oxidation to UDPGA |
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Term
| What occurs in step 3 of the glucuronidation pathway? |
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Definition
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Term
| What are the 4 glucuronides can be formed in glucuronidation pathway? |
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Definition
| C-, O-, N-, S-glucuronidation |
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Term
| How many steps are there in the Sulfate Conjugation Pathway? |
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Definition
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Term
| What occurs in steps 1 & 2 in the sulfate conjugation pathway? |
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Definition
| sulfate activation of PAPS |
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Term
| What occurs in step 3 of the sulfate conjugation pathway? |
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Definition
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Term
| What are the 2 elements that can sufate conjugate? |
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Definition
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Term
| How many steps are there in the Glutathione Conjugation Pathway? |
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Definition
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Term
| What are the 4 steps in the GSH Conjugation Pathway? |
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Definition
1) GST (transferase)
2) GGT (gamma-glutamyl transpeptidase)
3) DP (dipeptidase)
4) NAT (n-acetyltransferase) |
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Term
| What are 3 examples of gSh conjugation rxns? |
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Definition
CDNB (removes Cl)
DEM (removes double bond)
epoxides (open ring)
-adds an SG |
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Term
| What 3 factors affect drug metabolism? |
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Definition
Induction
Inhibition
Genetic polymorphisms |
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Term
| When might a person have increased de novo synthesis of CYP450? |
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Definition
| exposure to certain drugs & environmental pollutants. |
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Term
| What does increased CYP450 (induction) cause? |
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Definition
| increased biotransformation & therefore decrease in the availability of drug, possibly increased toxicity (if metabolized active). |
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Term
| How does CYP induction occur thru the pregnane X receptor (PXR)? |
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Definition
| nuclear receptor-mediated signal transduction |
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Term
| What occurs as a result to inhibition of drug biotransformation enzymes? |
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Definition
| elevated levels of the parent drug, prolonged effects, increased toxicity |
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Term
| Due to genetics, how are people classified based on their metabolic capacity? |
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Definition
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Term
| Which metabolism category puts a patient at a higher risk for adverse effects? |
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Definition
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