Genetics of CYP450's (part 2) Flashcards
What is CYP2A6 known as?
Nicotine C oxidase
Confirmed by Gonzalex and colleagues in 1989 by cloning it.
List some substrates of CYP2A6.
- Halothane
- Valproic acid
- Disulphiram
- Nicotine
- Procarcinogens (aflatoxin and nitrosamines)
- Coumarin
What is the major pathway of nicotine metabolism?
Conversion to cotinine
What role did CYP2A play in the 1980s?
Established as coumarin-7-hydroxylase
What was discovered about CYP2A6 in 1990?
CYP2A6 cDNA variant lacked coumarin-7-hydroxylase activity due to amino acid substitution.
What percentage of Europeans lack CYP2A6 activity?
Approx. 0.2%
What is the allele CYP2A6*2 associated with?
No haem incorporation (L160H)
Relevant to Europeans.
What is the consequence of the CYP2A6*4 allele?
Large deletion leading to no enzyme synthesis
Relevant to East Asians.
What is CYP2B6’s emerging importance?
Metabolism of environmental chemicals
What is the result of the CYP2B6*28 polymorphism?
Protein truncation at arginine 378
Which CYP2B6 allele has higher Vmax values?
CYP2B6*4
What is the main function of CYP2C8?
Metabolizes important drugs related to diabetes, cancer, and malaria
CYP2C8*2 is mainly present in which population?
African populations
What activity does CYP2C8*3 exhibit with paclitaxel?
Reduced activity compared to wild-type
What is a characteristic of CYP2C9?
Involvement in 20% of hepatic CYP content
What is the most common CYP2C9 polymorphism?
CYP2C9*2 (Arg144Cys)
What percentage of Europeans have the CYP2C9*3 polymorphism?
8%
CYP2C9 polymorphisms are particularly relevant for which drugs?
- Warfarin
- Phenytoin
What is the significance of the CYP3A4 enzyme?
Most important member of the CYP3A subfamily
What polymorphism is associated with decreased CYP3A4 activity?
CYP3A4*1B
What does CYP3A5*3 polymorphism affect?
Expression of CYP3A5
When is CYP3A7 expressed?
After 50-60 days of gestation up to 6 months post-natal age
What is CYP3A7’s role in metabolism?
Metabolizes endogenous substrates and xenobiotics reaching the fetus
What is the impact of the CYP3A7*2 allele?
Encodes an enzyme with moderately higher activity than CYP3A7*1
What is the polymorphism CYP3A7*2?
Encodes an enzyme with moderately higher activity than CYP3A7*1
Found in 82% of Caucasians, lower in Asians and Africans. Its impact on fetal drug clearance is unclear.
What mutation does CYP3A7*3 represent?
Frameshift mutation
What is unique about CYP3A7*1L?
Results from mRNA containing 13 exons of CYP3A7 and additional exons from CYP3AP1 at the 3’ end, formed by splicing between CYP3A7 and pseudogene CYP3AP1
What does CYP3A7*1C polymorphism affect?
This polymorphism results in the relevant expression of CYP3A7 in adult liver and favors DHEA metabolism over DHEA sulfate
Metabolizes DHEA with a 4-fold preference.
What was found in the study by Basci et al, 2007 regarding CYP3A7 polymorphism?
Decreased bone density in patients but not dependent on the relationship between bone density and DHEAS levels
What is the molecular basis of variation in CYP3A activity?
Not fully explained, with small contributions from *2 and *22 alleles likely due to their rarity
What role does PXR play in CYP3A expression?
Regulates CYP3A expression and may contribute to variations in activity
How is CYP3A7 expressed compared to CYP3A5?
CYP3A7 is expressed at higher levels in the liver than CYP3A5
What does the SNP screening of PXR reveal?
Identifies novel SNPs that affect transactivation but have very low frequency
What is the significance of the -2500 and -25000 regions in relation to PXR?
-2500 refers to the ATG start site; -25000 is close to the promoter region (350 bp away from transcription start site)
What is the purpose of the erythromycin breath test?
To measure labeled CO2 expired air following administration of 14C labeled erythromycin
What does the study by Andrews et al, 2010 involve?
Expression study using HepG2 cell line transfected with luciferase gene constructs
What is CYP1A1 and where is it usually detectable?
An extrahepatic enzyme usually only detectable in individuals exposed to an inducer like tobacco smoke
What does EROD stand for?
Ethoxy resorufin O-de-ethylase
What is the basis of CYP1A1 induction polymorphism?
Polymorphisms in the coding region of CYP1A1 detected but do not correlate with induced activity
What polymorphisms are detected in the Ah receptor?
Arg554Lys and Val570Ile
What is the allele frequency of the codon 554 polymorphism in Europeans?
0.11
What does the GWAS study on caffeine consumption reveal?
Compares coffee intake with each SNP, showing significant AhR signal in linkage disequilibrium
How is CYP1A1 silenced in prostate cancer?
Due to hypomethylation of the CYP1B1 promoter
What does the 3’UTR of CYP1B1 suggest?
Contains regions of extreme interspecies conservation, indicating potential mRNA regulation
What is the significance of the CYP1A2 SNPs in caffeine metabolism?
Most significant SNP is within the promoter region affecting inducibility and enzyme activity
What does CYP1A2*F mutation influence?
Inducibility of the gene and increases in vivo caffeine metabolism after smoking and omeprazole
What is the role of the Ah receptor polymorphism in caffeine intake?
Most significant SNP is far upstream, affecting caffeine metabolism
