PED3014 L3 Genetics of the cytochromes P450

which P450s show absence of activity in some individuals

• CYP2D6

• CYP2C19

• CYP2A6 - rare

• CYP3A5 -common

which P450s show increased activity in some individuals

• CYP2D6

• CYP1A1

• CYP2E1

• CYP2C19

which P450s show decreased activity in some indiciduals

• CYP2C9

• CYP3A4

• CYP1A2

• CYP2D6 - common

• CYP2C19 - common

where is the position of oxidation for CYP2D6

5-7 Amperes from the basic nitrogen

debrisoquine is almost extensively metabolised by…

CYP2D6 to form 4-OHD

give examples of CYP2D6 alleles with loss of activity

• CYP3D6×4 splicing defect

• CYP2D6×3 frameshift

• CYP2D6×5 CYP2D6 deletion

give examples of CYP2D6 alleles with reduced activity

CYP2D6×9 K281 deletion, loss of lysine residue

give an example of CYP2D6 alleles associated with increased activity

amplifications n=2,3,4,5 or 13 of CYP2D6

CYP2D6 gene rearrangements

X is Xba1 restiction site in wild type, distance between sites is 29kb

• distance between sites increases with amplification and decreases with deletion

CYP2D6×4 mutant at intron 3 exon 4 leads to

a truncated protein, incorrect amino acids, premature stop codon

CYP2D6×5 entire CYP2D6 gene is deleted which means

no protein is synthesised

CYP2D6×3 mutation causes

frameshift, incorrect amino acids, premature stop codon

CYP2D6×6 allele mutant causes

frameshift, non-functional protein synthesised

variations in CYP2D6 polymorphisms between populations

• europe - * 3,4,5, 6 common

• africa - * 4, 5, 17(reduced activity) common

Amplification more common in southern europe and africa

CYP2C19 found at relatively low concentrations in the

liver

CYP2C19 drug substrates

• omeprazole

• diazepam

• clopidogrel

• proguanil

what is CYP2C19 also known as

mephenytoin hydroxylase

3% of europeans and … lack CYP2C19 activity

20% of East Asians

CYP2C19×2

splicing defect

CYP2C19×3

stop codon

CYP2C19×4

GTG initiation codon- no transcription initiated

CYP2C19×17 increased activity

not gene duplication, polymorphism in upstream control sequence

CYP2C19×17 upstream polymorphism results in higher activity due to more gene transcription…

faster metabolism of both omeprazole and mephenytoin

basis of CYP2C19×17 effect

TXF GATA interacts with sequence homologous to *17

• probably represents increased txn of CYP2C19 gene in positive subjects