531 Lec 16-17

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

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•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

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• Can noncovalent or mechanism based covalent inhibition of an activated substrate

AHR Induction Pathway

AHR= Aryl hydrocarbon receptor

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1)Binding of inducer ligand to the cytosolic receptor

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2)Translocation of the ligand receptor complex to the nucleus via pore protein

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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

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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,

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Inducer: TCDD, 3 Methylcholanthrene

List the receptors and inducers for CYP3A4 induction

PXR receptor

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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 :(

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•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

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•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

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•Both a substrate and inhibitor because it can be converted by CYP3A4 to a nitroso containing potent inhibitor

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•Mechanism based inhibitor

Grapefruit juice Inhibition of CYP3A4

•contains aromatic compounds such as dihydroxybergamottin that inhibit CYP3A4

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•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

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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

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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