CYP3A5 Polymorphism, Amlodipine and Hypertension

REVIEW CYP3A5 polymorphism, amlodipine and hypertension

Y-P Zhang1,2, X-C Zuo2, Z-J Huang2, J-J Cai1,2,JWen1,2, DD Duan3 and H Yuan1,2

As a major cardiovascular risk factor for stroke, coronary artery disease, heart failure and end-stage renal disease, hypertension affects approximately one billion people and causes large economic burden worldwide. Cytochrome P450 3A5 (CYP3A5), belonging to the CYP3A subfamily, has been implicated in the regulation of blood pressure and may serve as a potential risk factor for the development of hypertension. Increased CYP3A5 activity could cause sodium and water retention by affecting the metabolism of cortisol in the kidneys. Furthermore, polymorphic CYP3A5 genotypes have been shown to cause differences in blood pressure response to antihypertensive drugs. Several studies have investigated the role of CYP3A5 in blood pressure response to amlodipine. However, recent data on the role of CYP3A5 in hypertension development and treatment are inconsistent. This review summarizes what is known regarding the relationship of CYP3A5 with hypertension, discusses the limitations in present studies, highlights the gaps and directs research to this ﬁeld.

Journal of Human Hypertension (2014) 28, 145–149; doi:10.1038/jhh.2013.67; published online 18 July 2013 Keywords: CYP3A5; polymorphism; blood pressure; amlodipine

INTRODUCTION of CYP3A5*1 carriers were higher than those of CYP3A5*3/*3 A large number of candidate genes have been shown to be individuals; CYP3A5 protein expression was conﬁned to the associated with hypertension.1–7 Cytochrome P450 3A5 (CYP3A5), proximal tubule. Givens et al.12 analyzed 25 black kidney donors belonging to the CYP3A subfamily, is expressed in the liver and found that the average CYP3A5 content in kidney microsomes and small intestine of all individuals8,9 and is predominant in from CYP3A5*1/*3 individuals exceeded that from CYP3A5*3/*3 the kidney.10–12 In contrast to the functional CYP3A5*1 allele, the individuals; the mean microsomal CYP3A activity is 18-fold higher CYP3A5*3 variant has a mutation in intron 3 that leads to the in CYP3A5*1/*3 kidneys than in CYP3A5*3/*3 kidneys. The CYP3A5 production of an aberrant mRNA and a truncated protein.13,14 polymorphism already reaches the Hardy–Weinberg equilibrium Recently, the polymorphic CYP3A5 has been reported to be in different ethnic populations.12,15,17,27,28 About 70% of the black implicated in the regulation of blood pressure and may serve as a potential risk factor for hypertension development.12,15–17 CYP3A5 population and 30% of the white and yellow populations possess converts cortisol to a 6b-hydroxylated metabolite, which could the CYP3A5*1 allele. The CYP3A5*1 allele frequency among blacks 18–21 exceeds those among all other ethnic populations studied to cause sodium and water retention in animals. However, the 9,12,15,17,24 effect of 6b-hydroxycortisol on sodium handling in humans has date. The variation in the frequency of the CYP3A5*3 not been examined. Current results regarding the association allele implies a complementary pattern between CYP3A5*1 and between CYP3A5 and hypertension in humans are still inconsistent CYP3A5*3. This variation is positively correlated with the (summary in Table 1). Polymorphic CYP3A5 genotypes have been geographical distance from the equator, and CYP3A5*1 could confer a selective advantage in the equatorial population shown to cause differences in blood pressure response to 24,29 13,22,23 experiencing water shortage by increasing sodium retention. antihypertensive drugs. To date, some studies have 12 evaluated the role of the CYP3A5 genetic polymorphism in Givens et al. reported for the ﬁrst time in 2003 that in a group antihypertensive effectiveness of amlodipine in humans. This of 25 healthy African-American adults consisting of 16 normo- review will discuss the role of the CYP3A5 polymorphism in tensive and 9 mildly hypertensive individuals, those possessing hypertension development and in the variability of amlodipine the CYP3A5*1/*1 genotype exhibited higher systolic blood effectiveness. pressure (SBP), mean arterial blood pressure and creatinine clearance (Cockcroft–Gault). The author, considering the role of CYP3A5 in mediating the 6b-hydroxycortisol and 6b-hydroxycorticosterone product,30,31 speculated that a high CYP3A5*1 allele CYP3A5 POLYMORPHISM AND HYPERTENSION frequency among African Americans may contribute to a high To our knowledge, CYP3A5 is expressed in the liver and small prevalence of sodium-sensitive hypertension in this population. intestine of all individuals.8,9 Recently, some studies illustrated that The limitation of this study is the small sample size, which is more the CYP3A5*1 allele is associated with CYP3A5 expression in likely to cause bias. Later, the data from 238 Japanese male human kidneys.24,25 Bolbrinker et al.26 analyzed sections of normal workers showed that the CYP3A5 genotype associated only with kidney tissue obtained from 93 white individuals undergoing diastolic blood pressure (DBP) and that the CYP3A5*1/*1 group nephrectomy and found that mRNA and protein expression levels had a DBP higher by 7 mm Hg compared with the CYP3A5*3/*3

1Department of Cardiology, the Third Xiang-Ya Hospital, Central South University, Changsha, People’s Republic of China; 2Center of Clinical Pharmacology, the Third Xiang-Ya Hospital, Central South University, Changsha, China and 3Laboratory of Cardiovascular Phenomics, the Department of Pharmacology, University of Nevada School of Medicine, Reno, NV, USA. Correspondence: Professor H Yuan, Department of Cardiology, Center of Clinical Pharmacology, The Third Xiang-Ya Hospital, Central South University, 138 Tong- Zi-Po Road, Changsha, Hunan 410013, People’s Republic of China. E-mail: [email protected] Received 10 March 2013; revised 12 June 2013; accepted 13 June 2013; published online 18 July 2013 CYP3A5 polymorphism in hypertension Y-P Zhang et al 146 elevated, but untreated, blood pressure from the University of Table 1. Summary of studies for association between CYP3A5 Erlangen–Nuremberg in Germany. Fromm et al.33 found that polymorphism and blood pressure individuals with the CYP3A5*1/*1 genotype had lower SBP and Study N Ethnicity Country CYP3A5*3/*3 that the CYP3A5 polymorphism did not affect DBP. There was no association of CYP3A5 genotypes with angiotensin II plasma SBP DBP concentration and urinary sodium excretion, but the CYP3A5*3/*3 group had lower serum aldosterone.33 A large population-based Givens12 25 Black USA kk study by Kreutz et al.34 showed that the CYP3A5*1 allele was Zhang17 238 Yellow Japanese — k 15 associated with both lower SBP and lower pulse pressure (PP), Ho 438 White USA — — whereas DBP was not affected by the CYP3A5*1 allele in the 72 Black India mm 32 Caucasian population in the Netherlands, which is consistent Lieb 1084 White Germany — — 33 34 Kivisto16 373 White Finland kk with the result reported by Fromm et al. Kreutz et al. also Fromm33 115 White Germany m — found that only in male CYP3A5*1 allele carriers was 24-hour Kreutz34 6777 White Netherland m — sodium excretion lower compared with individuals having the Bochud35 375 Black India kk CYP3A5*3/*3 genotype. However, in this study the sample size of Eap36 373 Black Seychelles — — the CYP3A5*1/*1 genotype was too small to perform a conclusive Coto37 500 White Spain — — 38 analysis because of the low frequency of the CYP3A5*1 allele in the Xi * 9076 — — Caucasian population. Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure. The data from different populations in different countries are k represents individuals with CYP3A5*3/*3 genotype having lower SBP or conflicting. A study including 375 individuals from 72 African DBP than CYPA5*1 carriers; mrepresents individuals with CYP3A5*3/*3 families in India showed that CYP3A5*1 carriers had a higher age- genotype having higher SBP or DBP than CYPA5*1 carriers; —represents no and sodium-related increase in ambulatory blood pressure com- difference between CYP3A5*3/*3 individuals and CYPA5*1 carriers. * means pared with non-carriers.35 Eap et al.36 reported that CYP3A5*3 and that conclusion came from the meta-analysis. CYP3A5*1 showed no association with ambulatory blood pressure among individuals of East-African descent in Seychelles islands. A study performed among pregnant women illustrated that the group.17 The author of this study, L Zhang, concluded that those allele and genotype frequencies of CYP3A5 did not differ between workers with the CYP3A5*1 allele were not salt-sensitive, whereas hypertensive and normotensive women, and variation in CYP3A5 the subjects with the CYP3A5*3/*3 genotype were more did not contribute to the risk for hypertension during pregnancy.37 vulnerable to salt intake, which is in contrast to the result Given the limited sample size, a meta-analysis including 10 reported by Givens.12,17 L Zhang assessed the daily sodium intake studies was performed to evaluate the association between the of individuals by analyzing 24-hour urinary sodium excretion in CYP3A5 polymorphism and blood pressure. Under a random-effect this study. However, 24-hour urinary sodium excretion changed model no association was observed among them.38 Even in the according to daily salt intake. Random tests of 24-hour urinary subgroup analysis of groups stratified by ethnicity, the meta- sodium excretion might not reflect long-term sodium intake. In analysis result showed that there was no relationship between the addition, salt-sensitive subjects have sodium and water retention. CYP3A5 polymorphism and hypertension in either white or black As they take in more salt and excrete less sodium, urinary sodium populations.38 However, CYP3A5*1 allele carriers had lower SBP could not accurately reflect the salt intake. compared with non-carriers.38 A much larger and comprehensive study performed by Ho The CYP3A5 polymorphism has attracted increasing attention in et al.15 demonstrated that there was no significant difference in the blood pressure regulation because of both previous animal distribution of CYP3A5 genotypes between hypertensive and experimental evidence and the potential mechanism of hyperten- normotensive subjects. However, in a subgroup the CYP3A5*1 sion development mediated by CYP3A5. Imaoka and Funae39 allele was significantly more common in 111 hypertensive blacks reported that the content of CYP3A in hepatic microsomes was than in 62 normotensive blacks. Blood pressure comparisons 140% higher in spontaneously hypertensive rats (SHR) than in involving whites showed no association with the CYP3A5 normotensive control rats (Wistar Kyoto rats, WKY). Ghosh et al.20 genotypes.15 A subgroup analysis including 72 black subjects demonstrated that renal microsomal CYP3A catalytic activity showed that the CYP3A5*3/*3 group had higher SBP and DBP was increased and consistent with increased urinary compared with the CYP3A5*1/*1 group.15 The limitation for this 6b-hydroxycortisol in SHR, which addressed the possibility that subgroup analysis is that the prevalence of hypertension in the increased renal CYP3A content may be a mechanism for CYP3A5*3/*3 group was not parallel to that in the CYP3A5*1/*1 hypertension in SHR. In a subsequent study,21 increase in CYP3A group for blacks (66.67% vs 40.74%, Po0.05). Only the CYP3A5*3/*3 catalytic activity and cortisol 6b-hydroxylation product in SHR group had a very small sample size. Although both Givens and Ho was confirmed. The CYP3A-selective inhibitor troleandomycin researched the relationship between CYP3A5 polymorphism and could lower 6b-hydrocortisol and blood pressure.21,30 Thus, it is blood pressure in the same ethnic subjects, contradictory possible that excessive intrarenal conversion of cortisol into conclusions were obtained. The small sample size might be a 6b-hydroxycortisol by increased renal CYP3A activity enhances major and potential explanation for the opposite results. However, post-renal proximal tubular sodium reabsorption and thus results the data from the Japanese workers partly supported Givens’ result. in elevated blood pressure level.20,21,30 However, increased The four studies performed in the Caucasian population also CYP3A activity could also protect blood pressure against showed inconsistent results. Data from 1084 Caucasian–German aldosterone-induced active sodium transport in kidney cells by residents from the Augsberg area supported no association converting corticosterone into 6b-hydrocorticosterone, which between CYP3A5*1 and hypertension after adjustment for age, could then lead to decreased blood pressure40 (Figure 1). All the gender and body mass index.32 A study conducted in Finland current animal evidence is from the SHR model, which only showed that the CYP3A5*1/*3 genotype had a significantly higher reflects a rare subtype of human hypertension inherited in a prevalence of hypertension among elderly Caucasians than did Mendelian manner.41 the CYP3A5*3/*3 genotype.16 Fromm et al.33 used the ambulatory Currently, the data on the association of CYP3A5 polymorphism 24-hour blood pressure monitor method to assess the relationship with hypertension in human trials are relatively limited and between CYP3A5 genotypes and hypertension. In this study they inconsistent. There are several potential explanations for these recruited 115 Caucasian male students with normal or mildly presently contradictory results. The populations studied are from

Journal of Human Hypertension (2014) 145 – 149 & 2014 Macmillan Publishers Limited CYP3A5 polymorphism in hypertension Y-P Zhang et al 147 different ethnicities and it is possible that the effects of CYP3A5 CYP3A activity in vivo.43,45 Polymorphic CYP3A5 genotypes may vary depending on the genetic context and physiological have been shown to cause pharmacokinetic and pharmaco- background because of the strong interethnic differences in the dynamic differences in CYP3A substrates, including saquinavir,46 CYP3A5*1 allele frequency. Even within the same ethnic group, midazolam,47 alprazolam,48 clopidogrel49 and verapamil.50,51 Ho people have different demographic characteristics, diet habits and et al.15 found that it was harder to control the blood pressure of living environments. The current inconsistent results might be at hypertensive individuals with the CYP3A5 *1/*1 genotype than of least partly explained by the interaction between genetic and those with the CYP3A5*3/*3 genotype. Amlodipine acting as a environment factors, as the phenotype of hypertension may be substrate of CYP3A could effectively and substantially lower blood substantially affected by the environment.42 Furthermore, the pressure but there is marked variability among individuals.52–56 gene–gene interaction might be a reason for the present Currently, several studies have evaluated the role of the CYP3A5 contradictory results.36 The interaction between CYPA5*1 and genetic polymorphism in the disposition and antihypertensive MDR1 (multidrug resistance 1) 3435T alleles on ambulatory blood effectiveness of amlodipine in humans. pressure has been reported. MDR1 may affect the association of Forty healthy male Korean participants were enrolled to assess the CYP3A5 polymorphism with hypertension. In addition, the the effect of CYP3A5 genotypes on amlodipine. In this study sample size of the association studies needs to be taken into CYP3A5*1 carriers had 20% lower oral clearance, higher mean area account. It should be noted that our understanding of the genetic under the plasma concentration–time curve and higher peak- determinants and pathogenesis of hypertension is still limited. plasma concentration compared with CYP3A5*3/*3 subjects.57 Further studies to clarify the role of CYP3A5 as a possible Blood pressure and pulse rate were not significantly different hypertension susceptibility gene are needed. between the two groups within 144 h after dosing with 5 mg amlodipine.57 We investigated the effect of the CYP3A5 polymorphism on the pharmacokinetics of amlodipine in CYP3A5 POLYMORPHISM AND BLOOD PRESSURE RESPONSE healthy Chinese volunteers and found that the result was TO AMLODIPINE consistent with that from healthy Korean participants (data not CYP3A4 is widely considered to be the dominant CYP3A isoform, shown). We also studied the relationship between the CYP3A5 but recently this view has been challenged by data indicating that polymorphism and the antihypertensive effectiveness of the relative contribution of CYP3A5 to the total CYP3A pool amlodipine in 75 hypertensive patients with renal transplant. may be much larger than previously assumed in individuals CYP3A5*3/*3 individuals showed the greatest decrease in DBP with increased levels of CYP3A5.8,24,43,44 The CYP3A5*3 allele after 24 weeks of amlodipine treatment (Figure 2). Our findings may thus contribute to observed interindividual variability in indicated that the CYP3A5 polymorphism had a significant effect on the decrease in DBP. Bhatnagar et al.58 did not find any association between CYP3A5 genotypes and the risk of reaching the blood pressure target among the early hypertensive African- American participants with amlodipine treatment. Because the CYP3A5*3 allele is not common among African Americans, this study had limited power. If CYP3A5 has a substantial role in the disposition of amlodipine, the amlodipine level in subjects with a defective CYP3A5 gene (for example, CYP3A5*3) should be higher than that in those with a normal allele. CYP3A5*3/*3 individuals with amlodipine treatment should have a greater reduction in blood pressure compared with CYP3A5*1 carriers. We already proved that the CYP3A5*3/*3 genotype induced a greater decrease in blood pressure in Chinese hypertensive patients with amlodipine treatment. The possible explanation for the conflicting results between our study and that by Bhatnagar et al. is that the pharmacological response of amlodipine may be influenced by ethnicity as a result of genetic factors, environmental factors and their interaction. Unexpectedly, Figure 1. CYP3A5-mediated contradictory mechanisms in the the present data on the pharmacokinetics of amlodipine showed regulation of blood pressure in kidneys. Increased CYP3A5 activity contributes to hypertension by enhanced sodium reabsorp- that the CYP3A5*1 carriers exhibited higher plasma levels of tion mediated by 6b-hydroxycortisol. Increased CYP3A5 activity amlodipine compared with CYP3A5*3/*3 subjects, suggesting that might protect blood pressure against aldosterone-induced the metabolism of amlodipine is faster and CYP3A enzyme activity active sodium transport by converting corticosterone into is higher in subjects with the CYP3A5*3/*3 genotype. Thus, there 6b-hydroxycorticosterone. might be other factors linked to CYP3A5 that have a greater

Figure 2. Association of CYP3A5 genotypes with blood pressure response to amlodipine. The bars represent means of reduction in blood pressure among different groups 24 weeks after amlodipine treatment. *P40.05 versus CYP3A5*1/*1 group, #Po0.05 versus CYP3A5*1/*1 group.

& 2014 Macmillan Publishers Limited Journal of Human Hypertension (2014) 145 – 149 CYP3A5 polymorphism in hypertension Y-P Zhang et al 148 impact on the plasma level of amlodipine than the defective ACKNOWLEDGEMENTS CYP3A5 gene directly. In addition to CYP3A5*3, other CYP3A5 This work was supported by the National Basic Research Program of China (No. polymorphisms have been identified that cause a decrease in or 2011CB512001), the National Natural Science Foundation of China (NO. 81273594), loss of enzyme activity. These polymorphisms might influence the the National Natural Science Foundation of China (NO. 81102512) and the Doctoral disposition of amlodipine more profoundly.9,24 Some studies Research and Innovation Project of Hunan Province (No. CX2011B075). have revealed a significant difference in the disposition of CYP3A substrate between CYP3A5*1 carriers and CYP3A5*3/*3 REFERENCES subjects.46,59–61 On the other hand, because CYP3A4 is the most abundant form of the CYP3A enzyme, its effect on amlodipine 1 Timberlake DS, O’Connor DT, Parmer RJ. Molecular genetics of essential hyper- cannot be excluded. In addition, the CYP3A5 genotype is closely tension: recent results and emerging strategies. Curr Opin Nephrol Hypertens 2001; 10: 71–79. linked to CYP3A4 haplotypes and such a linked polymorphic 32,33 2 Puddu P, Puddu GM, Cravero E, Ferrari E, Muscari A. The genetic basis of essential CYP3A4 gene might explain the unexpected results. Because hypertension. Acta Cardiol 2007; 62: 281–293. 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