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

• Published in: Journal of applied physiology (1985) 2003-09, Vol.95 (3), p.1297-1300
• Main Authors: Givens, Raymond C, Lin, Yvonne S, Dowling, Amy L. S, Thummel, Kenneth E, Lamba, Jatinder K, Schuetz, Erin G, Stewart, Paul W, Watkins, Paul B
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Adults; African Americans; Alleles; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; Black or African American; Black People; Blood pressure; Blood Pressure - genetics; Blood Pressure - physiology; Body Mass Index; Cell structures and functions; Creatinine - blood; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Frequency; Genotype; Hispanic or Latino; Humans; Isoenzymes - biosynthesis; Isoenzymes - genetics; Kidney - enzymology; Kidneys; Male; Microsomes - enzymology; Middle Aged; Miscellaneous; Molecular and cellular biology; Oxidoreductases, N-Demethylating - metabolism; Polymorphism; Polymorphism, Single Nucleotide - genetics; Predictive Value of Tests; Sodium; White People
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.00322.2003

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 ).