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What is CYP450 Induction
Increase in enzyme concentration in cell, mostly due to receptor based signaling by effector molecules leading to increased transcription of CYP450
•Induction results in increased metabolism and clearance of CYP450 substrates
What is CYP450 Inhibition
decrease in enzyme activity in cell due to tight binding of inactive or slowly active substrates
• Can noncovalent or mechanism based covalent inhibition of an activated substrate
AHR Induction Pathway
AHR= Aryl hydrocarbon receptor
1)Binding of inducer ligand to the cytosolic receptor
2)Translocation of the ligand receptor complex to the nucleus via pore protein
3)Binding of AhR complex to  a transcription factor (ARNT) that binds to a DNA sequence specific response element (DRE or XRE) upstream of CYP1A1 and other genes
4)DNA binding recruits RNA polymerase which increases transcription and the number of enzyme molecules
List the receptors and inducers for CYP1A1 induction
AhR receptor,
Inducer: TCDD, 3 Methylcholanthrene
List the receptors and inducers for CYP3A4 induction
PXR receptor
Inducer: Carbamazepine, St John’s Wort
Be able to predict the clinical effects of inducers on the metabolism of drug substrates of the same isoform
CYP450 Inhibition is caused by interactions at the ______
active site of the heme protein
Ketoconazole Inhibition of CYP450
•an imidazole antifungal drug that inhibits a fungal CYP450 required for membrane function BUT also inhibits human CYP450s- Mainly CYP3A4 causing drug interactions :(
•Works by blocking substrate binding to heme protein (imidazole ring N binds to iron)
Ketoconzaole affects on drugs metabolized by CYP3A4
•Drugs that are metabolized by CYP3A4 show slower clearance in the presence of ketoconazole leading to higher serum levels which can cause toxicity
•Oral bioavailability of CYP3A4 metabolized drugs can be increased in the presence of ketoconazole because CYP3A4 in the GI tract is also potently inhibited
Erythromycin Inhibition of CYP3A4
Prodrug inhibitor
•Both a substrate and inhibitor because it can be converted by CYP3A4 to a nitroso containing potent inhibitor
•Mechanism based inhibitor
Grapefruit juice Inhibition of CYP3A4
•contains aromatic compounds such as dihydroxybergamottin that inhibit CYP3A4
•Oral bioavailability of CYP3A4 metabolized drugs can be increased in the presence of grapefruit juice becuase CYP3A4 in the GI tract is also potently inhibited
Diallyl Sulfide (DAS)
CYP1A1 substrates
Polyaromatic hydrocarbons
CYP1A1 Inducers
Dioxin
Benzopyrene
Cigarette smoke
CYP1A1 Inhibitors
None
CYP2D6 Substrate
Amitriptyline
Codeine
CYP2D6 Inducers
None
CYP2D6 Inhibitors
SSRIs (Fluoxetine, Paroxetine)
CYP2E1 Substrate
Acetaminophen
Halogenated Anesthetics
CYP2E1 Inducers
Ethanol
CYP2E1 Inhibitors
Diallysulfide
CYP3A4 Substrate
Cyclosporine A
Carbamazepine
CYP3A4 Inducers
Carbamazepine
St Johns Wort
CYP3A4 Inhibitors
Ketoconazole
Erythromycin
Grapefruit juice
Ritonavir
CYP1A1 receptor
AhR
CYP3A4 receptor
PXR
Poor metabolizers have …..
two copies of inactive alleles (CYP2D6)
Extensive metabolizers
at least one active copies of alleles (up to 2) (CYP2D6)
Intermediate metabolizers have…
one partially active and one inactive allele (CYP2D6)
Ultrarapid metabolizers have….
multiple copies of the CYP2D6*2
Most genetic differentiations between people is due to…
single nucleotide polymorphisms (SNPs)
Single nucleotide Polymorphisms (SNPs)
point mutations that are present at >1% of the human population
Linked SNPs
do not influence the gene but can still be associated by proximity with effects of gene variant
Causative SNPs
located in the region od DNA that affects the gene expression or activity
*Noncoding and coding
Noncoding Causative SNPs
in regulatory region and change expression of gene
Coding Causative SNPs
SNPs change amino acid sequence
Most genetic data is bias towards
Europeans
CYP2D6 ultrarapid metabolizer
Increased metabolism of tricyclics to less active compounds as compared with extensive metabolizers
Lower plasma concentrations will increase probability of pharmacotherapy failure
CYP2D6 extensive metabolizer
Normal metabolism of tricyclics
CYP2D6 intermediate metabolizer
Reduced metabolism of tricyclics to less active compounds as compared with extensive metabolizers
Higher plasma concentrations will increase the probability of side effects
CYP2D6 poor metabolizer
Greatly reduced metabolism of tricyclics to less active compounds as compared with extensive metabolizers
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Higher plasma concentrations will increase the probability of side effects
Considering that the breast cancer drug Tamoxifen is metabolized into its active form by CYP2D6, what group of people would this drug not be effective for?
Poor metabolizers