Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.
Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.
Department of Molecular and Cell Biology, University of Maryland at Baltimore, Baltimore, Maryland, USA.
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P
Kuehl
J
J
Zhang
Y
Y
Lin
J
J
Lamba
M
M
Assem
J
J
Schuetz
P B
PB
Watkins
A
A
Daly
S A
SA
Wrighton
S D
SD
Hall
P
P
Maurel
M
M
Relling
C
C
Brimer
K
K
Yasuda
R
R
Venkataramanan
S
S
Strom
K
K
Thummel
M S
MS
Boguski
E
E
Schuetz
D000483:Alleles; D017398:Alternative Splicing; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D044469:Racial Groups
D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A