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Printable Handouts
Navigable Slide Index
- CYP3A family
- CYP3A - % in human liver
- % drugs metabolized by CYP3A
- CYP3A locus on chromos. 7q21
- CYP3A4
- Heterog. hepatic CYP3A distribution
- CYP3A activity
- CYP3A in drug metabolism
- CYP3A4 - factors affecting activity
- CYP3A inhibition
- Screening for CYP3A inhibitors
- In vitro CY3PA metabolism assay
- Fast throughput CY3PA activity
- Reproducibility of CYP3A activity
- CYP3A catalytic activity
- CYP3A activation
- CYP3A activation by aNF
- Intestinal CYP3A
- Intestinal CYP3A4
- Intestinal CYP3A immunohist.
- CYP3A content in liver/intestine
- CYP3A4 in small intestine
- Intestinal CYP3A - gender effect
- CYP3A oral bioavailability
- CYP3A subst. - oral bioavailability
- Inhibition of intestinal CYP3A
- Drug interactions with midazolam
- Summary
- CYP3A4 genetics
- Ozdemir paradox
- CYP3A4 gene variants
- CYP3A5
- Polymorphic hepatic CYP3A5
- Polymorphic intestinal CYP3A5
- CYP3A5*3
- CYP3A5*3 inactivating allele
- CYP3A5*3 causative SNP
- All CYP3A5 inactivating alleles
- CYP3A5 geno./pheno. in whites
- CYP3A5 geno./pheno. in blacks
- CYP3A5 = 50% of hepatic CYP3A
- CYP3A5 = 50% of intestinal CYP3A
- Midazolam hydrox. - CYP3A5 geno.
- CYP3A5*3 allele frequencies
- CYP 3A4, 3A5 and 3A7
- Summary and conclusions
- CYP3A5/CYP3A4 activities
- CYP3A4/CYP3A5 catalytic activities
- CYP3A5 genotype effects in vivo
- CYP3A5 geno. - tacrolimus clear.
- CYP3A5 geno. - CsA clear.
- Conclusions
- CYP3A5 geno. - inhibitor drug inter.
- CYP3A4/3A5 azole Ki in vitro
- Effect of itraconazole on MDZ
- Conclusions in vivo interaction data
- CYP3A5 geno./in vivo pheno. (1)
- CYP3A5 geno./in vivo pheno. (2)
- CYP3A7
- CYP3As in fetal liver
- CYP3A7 mRNA in some adults
- CYP3A7*1C
- Effect of CYP3A7*1C genotype
- Screening for CYP3A4 induction
- CYP3A induction - drug interaction
- In vivo effects - CYP3A induction
- Screen - primary hepatocytes
- PXR
- PXR - tissue expression
- PXR - screening assays
- PXR - exogenous ligands
- PXR - endogenous ligands
- PXR - low affinity receptor
- PXR KO mice
- CAR
- VDR
- VDR ligand induces CYP3A
- CYP3A4 promoter regul. by VDR
- Activation of CYP3A4 by VDR
- Multiple nuclear hormone receptors
- Other CYP3A4 regulators
- Summary - sources of CYP3A
- MDR1 and CYP3A (1)
- MDR1 and CYP3A (2)
- Overlap in MDR1 & CYP3A4 subs.
- MDR1 regulates CYP3A induction
- MDR1 regulates CYP3A activity
- Summary - CYP3A regulation
- Summary - question
- Drugs withdrawn from market
- CYP3A in withdrawal of drugs
Topics Covered
- Role of CYP3A4, CYP3A5 and CYP3A7 in drug metabolism
- Gene expression
- Molecular mechanisms of regulation
- Enzyme induction and inhibition
- Polymorphic variation
- Inter-individual variation
- Drug-drug interactions
Links
Series:
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Therapeutic Areas:
Talk Citation
Schuetz, E. (2015, August 11). Why study the cytochrome P4503A (CYP3A) family? [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved November 23, 2024, from https://doi.org/10.69645/OEEG9372.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Erin Schuetz has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Why study the cytochrome P4503A (CYP3A) family?
A selection of talks on Biochemistry
Transcript
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0:00
Why study the Cytochrome P4503A family,
also known as the CYP3As?
0:10
First, The CYP3A family is the most abundant CYP in human liver.
When a bank of human livers was immuno-quantitated for the amounts of the major CYPs,
CYP3A was found to represent on average about 30 percent of total hepatic P450,
making it the dominant CYP in this tissue.
0:34
Secondly, not only is CYP3A the most abundant hepatic CYP,
but a survey of drug reactions demonstrated that CYP3As catalyzed
the metabolism of approximately 50 percent of all drugs in clinical use.
Thus, based on these criteria,
it could be argued that CYP3A is the most important CYP in human liver.
1:00
The CYP3A family is comprised of four genes,
which are all located in tandem on chromosome 7q21 to 22,
and span about 230kb of DNA.
The four CYP3A genes are CYP3A43,
CYP3A4, CYP3A5, and CYP3A7.
There are two pseudo genes located on the locus, CYP3AP1 and P2.
It is believed the hierarchy of importance of CYP3A
to metabolism is that 3A4 is the most important,
followed by 3A5, and 3A7 in fetal liver.
1:39
CYP3A4 was first isolated and called HL5,
then purified and called HLp or P450NF.
Two groups cloned the first human CYP3AcDNA, CYP3A4, and CYP3A3.
These cDNAs differed by only 14 nucleotides.
However, amplification with primers revealed that only CYP3A4 is significantly expressed.
Thus, original publications with any of this nomenclature are all
referring to the same CYP, now called CYP3A4.