Association between urinary 6β-hydroxycortisol/cortisol ratio and CYP3A5 genotypes in a normotensive population

Rais,Naushad; Hussain,Arif; Chawla,Yogesh  Kumar; Kohli,Krishan  K.

doi:10.3892/etm.2012.842

Association between urinary 6β-hydroxycortisol/cortisol ratio and CYP3A5 genotypes in a normotensive population

Authors:
- Naushad Rais
- Arif Hussain
- Yogesh Kumar Chawla
- Krishan K. Kohli
View Affiliations

Affiliations: Department of Biotechnology, Manipal University, Dubai, United Arab Emirates, Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India, Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Published online on: November 29, 2012 https://doi.org/10.3892/etm.2012.842
Pages: 527-532

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Genetic polymorphism of genes involved in renal salt handling and arterial vessel tone is considered to be one of the causes of hypertension. Numerous reports suggest that cytochrome P4503A5 (CYP3A5) catalyzes 6β‑hydroxylation of endogenous cortisol (CS), which is associated with sodium and water retention in the kidney and involved in the regulation of blood pressure. The purpose of the present study was to study the associations of single nucleotide polymorphisms in the CYP3A5 gene with the urinary 6β‑hydroxycortisol/cortisol (6β‑OH‑CS/CS) ratio considered as quantitative phenotypes. CS measurements of three hundred (n=300) healthy, normotensive North Indian individuals was performed on morning spot urine samples by high‑performance liquid chromatography. Furthermore, genotyping for CYP3A5*3 and CYP3A5*6 was performed by PCR‑RFLP. The results indicated a unimodal distribution of CYP3A phenotypes in the North Indian population. In further analysis, all the phenotypes were distributed into three groups, demonstrating low (n=75), intermediate (n=150) and high CYP3A activity (n=75) based on CS and 6β‑OH-CS levels and log 6β‑OH‑CS/CS ratios. The subjects in the low and high activity groups were genotyped for the CYP3A5*3 and *6 alleles. The present study demonstrated that the allele frequencies of CYP3A5*1 and *3 were 0.29 (95% CI, 0.22‑0.36) and 0.71 (95% CI, 0.64‑0.78), respectively. Notably, the frequency of normal homozygotes (CYP3A5*1/*1) was significantly higher in the high activity than the low activity group (11% vs. 5%). Similarly, the frequency of mutant homozygotes (CYP3A5*3/*3) was significantly higher in the low activity group than the high activity group (57% vs. 44%). The allele frequency of CYP3A5*3 was significantly higher in the low activity group (0.76) than the high activity group (0.67). The mean 6β‑OH‑CS/CS ratios were 110, 76 and 69 in wild‑type homozygotes (n=12), heterozygotes (n=62) and mutant homozygotes (n=76), respectively. The difference between the normal and mutant homozygotes was statistically significant (P<0.05). The CYP3A5*6 allele was absent from all the subjects genotyped. This is the first study to report the genetic polymorphism of CYP3A5 in a North Indian population and its association with urinary 6β‑OH‑CS/CS ratio reflecting the CYP3A phenotypes.

View Figures

View References

1.	Hunt CM, Watkins PB, Saenger P, et al: Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol. Clin Pharmacol Ther. 51:18–23. 1992. View Article : Google Scholar : PubMed/NCBI
2.	Ghosh S, Grogan WM, Basu A and Watlington C: Renal corticosterone 6 beta-hydroxylase in the spontaneously hypertensive rat. Biochim Biophys Acta. 1182:152–156. 1993. View Article : Google Scholar : PubMed/NCBI
3.	Watlington CO, Kramer LB, Schuetz EG, et al: Corticosterone 6 beta-hydroxylation correlates with blood pressure in spontaneously hypertensive rats. Am J Physiol. 262:F927–F931. 1992.PubMed/NCBI
4.	Kuehl P, Zhang J, Lin Y, Lamba J, et al: Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 27:383–391. 2001. View Article : Google Scholar : PubMed/NCBI
5.	Huang W, Lin YS, McConn DJ II, et al: Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos. 32:1434–1445. 2004. View Article : Google Scholar : PubMed/NCBI
6.	Bolbrinker J, Seeberg S, Schostak M, et al: CYP3A5 genotype-phenotype analysis in the human kidney reveals a strong site-specific expression of CYP3A5 in the proximal tubule in carriers of the CYP3A5*1 allele. Drug Metab Dispos. 40:639–641. 2012.PubMed/NCBI
7.	Haehner BD, Gorski JC, Vandenbranden M, et al: Bimodal distribution of renal cytochrome P450 3A activity in humans. Mol Pharmacol. 50:52–59. 1996.PubMed/NCBI
8.	Duncan RL, Grogan WM, Kramer LB and Watlington CO: Corticosterone’s metabolite is an agonist for Na⁺ transport stimulation in A6 cells. Am J Physiol. 255:F736–F748. 1988.
9.	Grogan WM, Fidelman ML, Newton DE, et al: A corticosterone metabolite produced by A6 (toad kidney) cells in culture: identification and effects on Na⁺ transport. Endocrinology. 116:1189–1194. 1985. View Article : Google Scholar : PubMed/NCBI
10.	Koch I, Weil R, Wolbold R, et al: Interindividual variability and tissue-specificity in the expression of cytochrome P450 3A mRNA. Drug Metab Dispos. 30:1108–1114. 2002. View Article : Google Scholar : PubMed/NCBI
11.	Xi B, Wang C, Liu L, et al: Association of the CYP3A5 polymorphism (6986G>A) with blood pressure and hypertension. Hypertens Res. 34:1216–1220. 2011.
12.	Langaee TY, Gong Y, Yarandi HN, et al: Association of CYP3A5 polymorphisms with hypertension and antihypertensive response to verapamil. Clin Pharmacol Ther. 81:386–391. 2007. View Article : Google Scholar : PubMed/NCBI
13.	Eap CB, Bochud M, Elston RC, et al: CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt. Hypertension. 49:1007–1014. 2007. View Article : Google Scholar : PubMed/NCBI
14.	Givens RC, Lin YS, Dowling AL, et al: CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. J Appl Physiol. 95:1297–1300. 2003. View Article : Google Scholar : PubMed/NCBI
15.	Zhang L, Miyaki K, Wang W and Muramatsu M: CYP3A5 polymorphism and sensitivity of blood pressure to dietary salt in Japanese men. J Hum Hypertens. 24:345–350. 2010. View Article : Google Scholar : PubMed/NCBI
16.	Rais N, Chawla YK and Kohli KK: CYP3A phenotypes and genotypes in North Indians. Eur J Clin Pharmacol. 62:417–422. 2006. View Article : Google Scholar : PubMed/NCBI
17.	Daly AK, Steen VM, Fairbrother KS and Idle JR: CYP2D6 multiallelism. Methods Enzymol. 272:199–210. 1996. View Article : Google Scholar
18.	Balram C, Zhou Q, Cheung YB and Lee EJ: CYP3A53 and 6 single nucleotide polymorphisms in three distinct Asian populations. Eur J Clin Pharmacol. 59:123–126. 2003.
19.	Aoyama T, Yamano S, Waxman DJ, et al: Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine. J Biol Chem. 264:10388–10395. 1989.
20.	Mugundu GM, Sallans L, Guo Y, et al: Assessment of the impact of CYP3A polymorphisms on the formation of α-hydroxytamoxifen and N-desmethyltamoxifen in human liver microsomes. Drug Metab Dispos. 40:389–396. 2012.
21.	Daly AK: Significance of the minor cytochrome P450 3A isoforms. Clinic Pharmacokinet. 45:13–31. 2006. View Article : Google Scholar : PubMed/NCBI
22.	Kamdem LK, Streit F, Zanger UM, et al: Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin Chem. 51:1374–1381. 2005. View Article : Google Scholar : PubMed/NCBI
23.	Givens RC, Lin YS, Dowling AL, et al: CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. J Appl Physiol. 95:1297–1300. 2003. View Article : Google Scholar : PubMed/NCBI
24.	Kornel L, Miyabo S, Saito Z, et al: Corticosteroids in human blood. VIII Cortisol metabolites in plasma of normotensive subjects and patients with essential hypertension. J Clin Endocrinol Metab. 40:949–958. 1975. View Article : Google Scholar : PubMed/NCBI
25.	Ho H, Pinto A, Hall SD, et al: Association between the CYP3A5 genotype and blood pressure. Hypertension. 45:294–298. 2005. View Article : Google Scholar : PubMed/NCBI
26.	Cornoni-Huntley J, LaCroix AZ and Havlik RJ: Race and sex differentials in the impact of hypertension in the United States. The National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. Arch Intern Med. 149:780–788. 1989. View Article : Google Scholar : PubMed/NCBI
27.	Weinberger MH: Salt sensitivity of blood pressure in humans. Hypertension. 27:481–490. 1996. View Article : Google Scholar : PubMed/NCBI
28.	Xie HG, Wood AJ, Kim RB, et al: Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics. 5:243–272. 2004. View Article : Google Scholar : PubMed/NCBI
29.	Lamba JK, Dhiman RK and Kohli KK: CYP2C19 genetic mutations in North Indians. Clin Pharmacol Ther. 68:328–335. 2000. View Article : Google Scholar : PubMed/NCBI
30.	Adithan C, Gerard N, Vasu S, et al: Allele and genotype frequency of CYP2C19 in a Tamilian population. Br J Clin Pharmacol. 56:331–333. 2003. View Article : Google Scholar : PubMed/NCBI