PED3014 L4 Genetics of the cytochromes P450

CYP2A6 is a relatively minor P450 in terms of

expression

CYP2A6 Substrates -prescribed drugs

• Halothane

• Valproic acid

• Disulphiram

CYP2A6 substrates (environmental)

• Nicotine (major pathway of nicotine to cotinine)

• Procarcinogens - aflatoxin and nitrosamines

• Coumarin - additive found in food and perfume

approx 0.2% of Europeans and 3% of…

East Asians lack CYP2A6 activity

CYP2A6 Alleles with no or decreased activity

• CYP2A6×2 no haem incorporated

• CYP2A6×4 No enzyme

• CYP2A6×5 unstable protein

CYP2A6 alleles with increased activity

evidence for additional CYP2A6 (wild-type) copies in some individuals

CYP2C9 Substrates tend to have areas of…

strong hydrogen bond forming potential

• ion pair formation 5-10 A from the site of metabolism, product is usually a hydroxylated substrate

typical CYP2C9 substrates

• Warfarin

• tolbutamide and sulphonyl ureas

• NSAIDs - ibuprofen, diclofenac

• Phenytoin

reduced activity CYP2C9 alleles

CYP2C9×2 and CYP2C9×3

CYP3A4 expressed at high levels in the liver and responsible for the metabolism of which drugs

• cyclosporin

• erythromycin

• mifedipine

• various steroids

CYP3A5 is expressed in

approximately 20% of livers

CYP3A4×22 C to T change in intron 6 appears to result in lower CYP3A4 mRNA and protein levels

allele frequency for T is 0.05 so approx 10% heterozygosity

CYP3A5 polymorphism- 90% of european CYP3A5 alleles have G6986 in intron 3

• results in creation of an aberrant splice site and 670bp insertion in mature hepatic mRNA

• leads to a nonsense protein

CYP3A pharmacogenetic description

• molecular basis of variation in CYP3A activity still not fully explained

• small contributions from *2 and *22 alleles likely tough effects small and alleles relitively rare

what is PXR polymorphism

• upstream and coding sequences of PXR screened for novel SNPs using sample of known phenotype

• coding region amino acid changes affect transactivation but frequency is very low

• variety of upstream and intron polymorphisms occur

• some evidence that phenotype may correlate with genotype for certain non-coding polymorphisms

CYP1A1 pharmacogenetics

• CYP1A1 is extrahepatic and usually only detectable in individuals exposed to an inducer e.g. tobacco smoke

• some individuals appear to have greater ability than others to induce CYP1A1

• can assay inducing ability by incubating lymphocytes with inducer in culture and then measuring CYP1A1

Basis of CYP1A1 Polymorphism

• polymorphisms giving amino acid substitutions in the coding region of CYP1A1 have been detected but dont correlate with induced activity either

• CYP1A1 induction is mediated by the Ah receptor

Polymorphism in the Ah receptor

• polymorphisms detected at 2 positions in the coding region (Arg554Lys and Val570Ile)

• codon 554 polymorphism has allele frequency of 0.11 in Europeans

• presence of variant codon 554 allele correlates with high induced CYP1A1 activity

Polymorphism in CYP1A2

• caffeine GWAS suggests CYP1A2 shows interindividual variation

• most significant CYP1A2 SNP is within the promoter region

• Ah receptor polymorphism also affects caffeine intake