Genetics of CYP450's (part 1) Flashcards
What types of substrates does CYP2D6 metabolize?
Cardiovascular agents, antipsychotics, antidepressants
Substrates have basic nitrogen ionized at physiological pH and a hydrophobic region
What percentage of polymorphisms in CYP2D6 lack enzyme activity?
5-10%
Due to polymorphisms in genes
What are the common alleles associated with poor metabolism in CYP2D6?
- CYP2D6*3
- CYP2D6*4
- CYP2D6*5
- CYP2D6*6
95% of Europeans are poor metabolizers and have 2 copies of any combination of these alleles
What is the consequence of mutations in CYP2D6?
Point mutations leading to splicing defects or deletions, resulting in truncated proteins or no protein synthesis
What is the prevalence of intermediate metabolizers in East Asians and African populations?
They are common and often heterozygous for inactivating mutations or homozygous for alleles associated with impaired metabolism
What was discovered about drug metabolism in the 1950s?
Many drugs undergo oxidative metabolism in the presence of molecular oxygen and NADPH in liver microsomes
Who described CYP450’s as a haemoprotein in 1962?
Omura and Sato
Displayed its peak at 450 nm in presence of carbon monoxide and dithionite
What did Robert and Michael discover in the mid-1970s?
Some individuals were unable to oxidize the drugs desbrisoquine and sparteine, confirming slow metabolism in 10% of Europeans
What significant discovery in the 1980s related to CYP2D6 occurred?
Evidence for gene polymorphisms in human CYP2D6 was revealed through Southern Blot experiments
What are the common defective CYP2D6 alleles?
- CYP2D6*3: A6986 base deletion
- CYP2D6*4: G to A change causing exon skipping
- CYP2D6*5: Entire gene deletion
- CYP2D6*6: T to G change causing frameshift
What is the role of CYP2C19 in drug metabolism?
It plays a role in bioactivation of drugs like cyclophosphamide, omeprazole, diazepam, proguanil, and clopidogrel
What is the effect of CYP2C19 polymorphisms on drug metabolism?
3% of Europeans and 20% of East Asians lack CYP2C19 activity, which can lead to impaired metabolism
What is the common allele associated with poor metabolism in CYP2C19?
CYP2C19*2
Present in 5% of Caucasians and Africans, and 20% of Asians with a splicing defect
What can happen to patients taking clopidogrel with defective CYP2C19 alleles?
They may have less effective responses due to the role of CYP2C19 in activating this pro-drug
What is the significance of CYP2D6 in the metabolism of tamoxifen?
CYP2D6 produces 4-hydroxy-N-desmethyltamoxifen (endoxifen), which is important for the biological response to tamoxifen
What are the potential consequences of having an ultrarapid metabolizer phenotype?
Increased risk of opioid intoxication or inadequate therapeutic response to medications
What is the gene-dose effect related to CYP2D6?
The number of active CYP2D6 alleles predicts enzyme activity levels, affecting drug metabolism
What is a potential future trend in drug development regarding CYP2D6?
The drug industry may avoid developing drugs heavily influenced by CYP2D6 polymorphism
Fill in the blank: The most common defective allele of CYP2D6 is _______.
CYP2D6*4
True or False: CYP2C19 is primarily responsible for the metabolism of antidepressants.
False
CYP2D6 is primarily responsible for the metabolism of many antidepressants
What is the prevalence of CYP2C19 poor metabolizers in Caucasians and Africans?
5%
Poor metabolizers are individuals who have genetic variations that reduce enzyme activity.
What genetic variant is associated with CYP2C19*3?
G636A
This variant introduces a stop codon, leading to loss of function.
Which genetic change is associated with CYP2C19*4?
GTG initiation codon - no transcription initiated
This variant prevents the formation of the enzyme.
What mutation is found in CYP2C19*5?
C1297T
This mutation leads to an amino acid change, R433W.
What is the mutation associated with CYP2C19*6?
G395A
This variant causes the amino acid change R123Q.
What defect is associated with CYP2C19*7?
Intron 5 T to A splicing defect
This defect affects the proper processing of the mRNA.
What genetic change is linked to CYP2C19*8?
T358C
This variant results in the amino acid change W120R.
What is the significance of CYP2C19*17?
Increased activity due to upstream polymorphism
This variant leads to faster metabolism of drugs like omeprazole.
What are the two SNPs associated with CYP2C19*17?
-806C>T and -3402C>T
These SNPs are located in the 5’ flanking region and affect gene expression.
What did Sim et al., 2006 study reveal about CYP2C19*17?
Homozygous subjects had different omeprazole AUC levels
The study observed significant variations in drug metabolism.
What did Rudberg et al., 2007 find about patients on escitalopram therapy?
42% lower plasma concentrations in CYP2C19*17 carriers
This suggests the need for dose adjustments in these patients.
What is the splice site difference between CYP2C191 and CYP2C192?
CYP2C191 has ag AT; CYP2C192 has ag GA
This affects the efficiency of splicing.
How much more frequent is CYP2C19*17 in Mediterranean-Southern Europeans compared to East Asians?
42-fold more frequent
This highlights population variability in genetic metabolism.
What transcription factor interacts with the base change in CYP2C19*17?
GATA
This interaction is part of the mechanism for increased gene transcription.
