Pharmacogenetics of Sult1A1

Daniels, Jaclyn; Kadlubar, Susan

doi:10.2217/pgs.14.134

Cited by 10 publications

(4 citation statements)

References 79 publications

(74 reference statements)

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“…The most common phase II biotransformation enzymes include sulfotransferases (SULTs), N-acetyltransferases (NATs), and methyltransferases (MTs). SULTs utilizes 3′-phospho-5′adenylyl sulfate (PAPS) as a sulfonate donor to catalyze the sulfate conjugation of a wide variety of acceptor molecules that bear a hydroxyl or an amine group (Daniels and Kadlubar, 2014). Sulfonation increases the water solubility of most compounds, and therefore their potential for renal excretion, but it can also result in bioactivation to form active metabolites.…”

Section: Discussionmentioning

confidence: 99%

SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population

Xie

Liu

et al. 2022

Front. Genet.

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Background: The purpose of this study was to identify genetic variations associated with the metabolism of dabigatran in healthy Chinese subjects, with particular focus given to pharmacokinetics (PK) and pharmacodynamics (PD).Methods: Healthy Chinese adults aged 18–65 years with unknown genotypes from a bioequivalence trial were included according to the protocol registered at ClinicalTrial.org (NCT03161496). All subjects received a single dose (150 mg) of dabigatran etexilate. PK (main outcomes: area under the concentration-time, AUC0-t, of total and free dabigatran) and PD (main outcomes: anti-FIIa activity, APTT, and PT) parameters were evaluated. Whole-exome sequencing and genome-wide association analyses were performed. Additionally, candidate gene association analyses related to dabigatran were conducted.Results: A total of 118 healthy Chinese subjects were enrolled in this study. According to the p-value suggestive threshold (1.0 × 10−4), the following three SNPs were found to be associated with the AUC0–t of total dabigatran: SLC4A4 SNP rs138389345 (p = 5.99 × 10−5), FRAS1 SNP rs6835769 (p = 6.88 × 10−5), and SULT1A1 SNP rs9282862 (p = 7.44 × 10−5). Furthermore, these SNPs were also found to have significant influences on the AUC0–t of free dabigatran, maximum plasma concentration, and anti-FIIa activity (p < 0.05). Moreover, we identified 30 new potential SNPs of 13 reported candidate genes (ABCB1, ABCC2, ABCG2, CYP2B6, CYP1A2, CYP2C19, CYP3A5, CES1, SLCO1B1, SLC22A1, UGT1A1, UGT1A9, and UGT2B7) that were associated with drug metabolism.Conclusion: Genetic variations were indeed found to impact dabigatran metabolism in a population of healthy Chinese subjects. Further research is needed to explore the more detailed functions of these SNPs. Additionally, our results should be verified in studies that use larger sample sizes and investigate other ethnicities.

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Section: Discussionmentioning

confidence: 99%

SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population

Xie

Liu

et al. 2022

Front. Genet.

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“…Although we did see a trend toward lower sulfation clearance in SULT1A1 *2/*2 individuals, this did not reach the statistical significance threshold in the univariate or multivariate analyses. The SULT1A1*2 variant has rarely been studied in the context of drug pharmacokinetics (Daniels and Kadlubar, 2014). Several studies have examined the association of SULT1A1*2 with the pharmacokinetics of tamoxifen and major oxidative metabolites (Jin et al, 2005;Gjerde et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers

Court

Zhu

Massé

et al. 2017

J Pharmacol Exp Ther

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Over 30 years ago, black Africans from Kenya and Ghana were shown to metabolize acetaminophen faster by glucuronidation and slower by oxidation compared with white Scottish Europeans. The objectives of this study were to determine whether similar differences exist between African-Americans and European-Americans, and to identify genetic polymorphisms that could explain these potential differences. Acetaminophen plasma pharmacokinetics and partial urinary metabolite clearances via glucuronidation, sulfation, and oxidation were determined in healthy African-Americans (18 men, 23 women) and European-Americans (34 men, 20 women) following a 1-g oral dose. There were no differences in acetaminophen total plasma, glucuronidation, or sulfation clearance values between African-Americans and European-Americans. However, median oxidation clearance was 37% lower in African-Americans versus European-Americans (0.57 versus 0.90 ml/min per kilogram; = 0.0001). Although acetaminophen total or metabolite clearance values were not different between genders, shorter plasma half-life values (by 11-14%; < 0.01) were observed for acetaminophen, acetaminophen glucuronide, and acetaminophen sulfate in women versus men. The UGT2B15*2 polymorphism was associated with variant-allele-number proportional reductions in acetaminophen total clearance (by 15-27%; < 0.001) and glucuronidation partial clearance (by 23-48%; < 0.001). UGT2B15 *2/*2 genotype subjects also showed higher acetaminophen protein-adduct concentrations than *1/*2 (by 42%; = 0.003) and *1/*1 (by 41%; = 0.003) individuals. Finally, CYP2E1 *1D/*1D genotype African-Americans had lower oxidation clearance than *1C/*1D (by 42%; = 0.041) and *1C/*1C (by 44%; = 0.048) African-Americans. Consequently, African-Americans oxidize acetaminophen more slowly than European-Americans, which may be partially explained by the CYP2E1*1D polymorphism. UGT2B15*2 influences acetaminophen pharmacokinetics in both African-Americans and European-Americans.

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“…The latter are phase-II detoxification enzymes and have a crucial role in the metabolism of several xenobiotics and endogenous compounds (eg, tamoxifen). 30 , 31 High polymorphism of SULT1A1 has been reported among Caucasian, Chinese, African–American and Korean populations. 32 , 33 Moyer et al reported that the genetic variation in SULT1A1 , including rs750155, which is located in the promoter region (the short arm of chromosome 16) of SULT1A1 , could explain (at least in part) the interindividual variability in the onset of menopause and symptoms before initiation of hormone therapy, and may represent a step towards individualizing decisions for hormone therapy.…”

Section: Discussionmentioning

confidence: 99%

Genetic Polymorphisms of Very Important Pharmacogene Variants in the Blang Population from Yunnan Province in China

Wang¹,

Peng²,

Lu³

et al. 2021

PGPM

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Background We aimed to enrich the pharmacogenomic information of a Blang population (BP) from Yunnan Province in China. Methods We genotyped 55 very important pharmacogene (VIP) variants from the PharmGKB database and compared their genotype distribution (GD) in a BP with that of 26 populations by the χ 2 test. The minor allele frequency (MAF) distribution of seven significantly different single-nucleotide polymorphisms (SNPs) was conducted to compare the difference between the BP and 26 other populations. Results Compared with the GD of 55 loci in the BP, among 26 studied populations, GWD, YRI, GIH, ESN, MSL, TSI, PJL, ACB, FIN and IBS were the top-10 populations, which showed a significantly different GD >35 loci. CHB, JPT, CDX, CHS, and KHV populations had a significantly different GD <20 loci. A GD difference of 27–34 loci was found between the BP and 11 populations (LWK, CEU, ITU, STU, PUR, CLM, GBR, ASW, BEB, MXL and PEL). The GD of five loci (rs750155 ( SULT1A1 ), rs4291 ( ACE ), rs1051298 ( SLC19A1 ), rs1131596 ( SLC19A1 ) and rs1051296 ( SLC19A1 )) were the most significantly different in the BP as compared with that of the other 26 populations. The genotype frequency of rs1800764 ( ACE ) and rs1065852 ( CYP2D6 ) was different in all populations except for PEL and LWK, respectively. MAFs of rs1065852 ( CYP2D6 ) and rs750155 ( SULT1A1 ) showed the largest fluctuation between the BP and SAS, EUR, AFR and AMR populations. Conclusion Our data can provide theoretical guidance for safe and efficacious personalized drug use in the Blang population.

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Pharmacogenetics of Sult1A1

Cited by 10 publications

References 79 publications

SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population

SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population

Race, Gender, and Genetic Polymorphism Contribute to Variability in Acetaminophen Pharmacokinetics, Metabolism, and Protein-Adduct Concentrations in Healthy African-American and European-American Volunteers

Genetic Polymorphisms of Very Important Pharmacogene Variants in the Blang Population from Yunnan Province in China

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