The cytochrome P450 3A (CYP3A) subfamily of enzymes comprises isoforms that catalyze metabolism of foreign or "xenobiotic" chemicals that include most marketed pharmaceuticals. CYP3A activities are also critical in clearing and altering the bioactivities of many endogenous molecules. Research into CYP3As has focused primarily on their roles in drug metabolizing; much less attention has gone to physiologic effects of CYP3A activities. I review here established and hypothesized physiologic roles for CYP3A enzymes.
I have specifically studied whether CYP3As modulate renal sodium transport and blood pressure. A single-nucleotide polymorphism (SNP; A6986G) in the CYP3A5 gene determines CYP3A5 apoprotein expression and enzyme activity. A6986G was shown to predict renal CYP3A expression and activity among human kidney samples mostly from Caucasians and to associate with blood pressure and renal function among African-Americans.
Genotyping for A6986G and additional expression-determining CYP3A5 SNPs (G14690A and 27131-32insT) was performed for a larger group of African-Americans. I show that genotypes at these loci can be computationally resolved into functional haplotypes, which may improve the ability of CYP3A5 SNPs to predict blood pressure and other phenotypes.
I used mouse kidney collecting duct cells to study effects of a product of CYP3A catalysis, 6β-hydroxycorticosterone. I show that 6β-hydroxycorticosterone inhibits activity and expression of 11β-hydroxysteroid dehydrogenase type 2, an enzyme that prevents glucocorticoids from inappropriately activating the mineralocorticoid receptor. 6β-hydroxycorticosterone also appears to antagonize mineralocorticoid receptor-mediated increases in expression of genes related to sodium transport.
Wild-type mice that were injected with 6β-hydroxycorticosterone failed to demonstrate greater sodium-sensitivity of blood pressure than did mice injected with vehicle. Mouse models were made to express human CYP3A5. Mice bearing a CYP3A5 transgene exhibited slightly higher blood pressures than did wild-type mice, an effect that may be sodium-dependent.
Finally, I performed a systematic review and meta-analysis of subsequent human studies of CYP3A5 genotype associations with blood pressure and hypertension. Considerable variability is apparent among these studies. Intriguing data emerge but summary statistics for suitable studies (primarily of healthy whites) show little evidence for significant association. I discuss the need for increased standardization among future studies and for greater inclusion of black subjects.
|Commitee:||Anderson, John, Beck, Melinda, Switzer, Boyd, Watkins, Paul|
|School:||The University of North Carolina at Chapel Hill|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 68/11, Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics|
|Keywords:||Cytochrome P450 3A, Genetics, Hypertension, Kidney, Race, Sodium transport|
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