CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults

1 General Clinical Research Center, University of North Carolina School of Medicine, Chapel Hill 27514; 2 Duke University School of Medicine, Durham, North Carolina 27705; 3 Department of Pharmaceutics, University of Washington, Seattle, Washington 98195; and 4 Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 Submitted 31 March 2003 ; accepted in final form 15 May 2003 ABSTRACT 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. cytochrome P -450 3A5; single-nucleotide polymorphism; kidney; sodium sensitivity Address for reprint requests and other correspondence: P. B. Watkins, 3005 APCF Bldg., Univ. of North Carolina Hospitals, 101 Manning Dr., Chapel Hill, NC 27514 (E-mail: pbwatkins{at}med.unc.edu ).