CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults.
A single-nucleotide polymorphism (A6986G) in the cytochrome p-450 3A5 (CYP3A5) gene distinguishes an expressor (*1) and a reduced-expressor (*3) allele and largely predicts CYP3A5 content in liver and intestine. CYP3A5 is the prevailing CYP3A isoform in kidney. We report that, among renal microsomes from 21 organ donors, those from *1/*3 individuals had at least eightfold higher mean kidney microsomal CYP3A5 content and 18-fold higher mean CYP3A catalytic activity than did those from *3/*3 individuals (P = 0.0001 and P = 0.0137, respectively). We also report significant associations between the A6986G polymorphism and systolic blood pressure (P = 0.0007), mean arterial pressure (P = 0.0075), and creatinine clearance (P = 0.0035) among 25 healthy African-American adults. These associations remained significant when sex, age, and body mass index were taken into account. The mean systolic blood pressure of homozygous CYP3A5 expressors (*1/*1) exceeded that of homozygous nonexpressors (*3/*3) by 19.3 mmHg. We speculate whether a high CYP3A5 expressor allele frequency among African-Americans may contribute to a high prevalence of sodium-sensitive hypertension in this population.
Givens
Raymond C
RC
General Clinical Research Center, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA.
Lin
Yvonne S
YS
Dowling
Amy L S
AL
Thummel
Kenneth E
KE
Lamba
Jatinder K
JK
Schuetz
Erin G
EG
Stewart
Paul W
PW
Watkins
Paul B
PB
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D044383:Black People; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology*; D015992:Body Mass Index; D003404:Creatinine / Q000097:blood; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006630:Hispanic or Latino; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000201:enzymology*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011237:Predictive Value of Tests; D044465:White People; D001741:Black or African American
D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D003404:Creatinine; D001189:Aryl Hydrocarbon Hydroxylases; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating