Copy number variation in sulfotransferase isoform 1A1 (SULT1A1) is significantly associated with enzymatic activity in Japanese subjects

Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
Pharmacogenomics and Personalized Medicine 03/2013; 6(1):19-24. DOI: 10.2147/PGPM.S36579
Source: PubMed


Sulfotransferase isoform 1A1 (SULT1A1) plays a key role in the metabolism of a variety of endo- and xenobiotics and it's activity could influence response to drugs. Our previous studies have focused on the impact of genetic variants of SULT1A1 on enzymatic activity in Caucasians and African-Americans. However, the contribution of genetic variants to SULT1A1 activity in Asians has not been explored. In this study, we investigated the collective effects of both SULT1A1 copy number variants (CNVs) and single nucleotide polymorphisms (SNPs) in the promoter region, coding region, and 3' untranslated region on SULT1A1 activity in Japanese subjects. SNPs in the SULT1A1 promoter and 3' untranslated region were not associated with SULT1A1 activity (P > 0.05). SULT1A1*1/2 (Arg213His) was marginally associated with SULT1A1 activity (P = 0.037). However, SULT1A1 CNVs were strongly associated with SULT1A1 activity (trend test P = 0.008) and accounted for 10% of the observed variability in activity for Japanese subjects. In conclusion, SULT1A1 CNVs play a pivotal role in determination of SULT1A1 activity in Japanese subjects, highlighting the influence of ethnic differences in SULT1A1 genetic variants on drug metabolism and therapeutic efficacy.

Download full-text


Available from: Ishwori B Dhakal, May 12, 2014
  • Source
    • "Although humans lack a direct ortholog of Sult3a1, the human sulfotransferase with the closest amino acid similarity is a phenol sulfotransferase called SULT1A1 (Brix et al. 1999; Gamage et al. 2006). Humans contain between one and five copies of SULT1A1 (Gaedigk et al. 2012; Hebbring et al. 2007; Yu et al. 2013) and our results suggest that copy number variation could be associated with the variation in benzene induced toxicity in humans. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Inhalation of benzene at levels below the current exposure limit values leads to hematotoxicity in occupationally exposed workers. objective: We sought to evaluate Diversity Outbred (DO) mice as a tool for exposure threshold assessment and to identify genetic factors that infuence benzene-induced genotoxicity. Methods: We exposed male DO mice to benzene (0, 1, 10, or 100 ppm; 75 mice/exposure group) via inhalation for 28 days (6 hr/day for 5 days/week). Te study was repeated using two independent cohorts of 300 animals each. We measured micronuclei frequency in reticulocytes from peripheral blood and bone marrow and applied benchmark concentration modeling to estimate exposure thresholds. We genotyped the mice and performed linkage analysis. Results: We observed a dose-dependent increase in benzene-induced chromosomal damage and estimated a benchmark concentration limit of 0.205 ppm benzene using DO mice. Tis estimate is an order of magnitude below the value estimated using B6C3F1 mice. We identifed a locus on Chr 10 (31.87 Mb) that contained a pair of overexpressed sulfotransferases that were inversely correlated with genotoxicity. Conclusions: The genetically diverse DO mice provided a reproducible response to benzene exposure. Te DO mice display interindividual variation in toxicity response and, as such, may more accurately refect the range of response that is observed in human populations. Studies using DO mice can localize genetic associations with high precision. Te identifcation of sulfotransferases as candidate genes suggests that DO mice may provide additional insight into benzene-induced genotoxicity. © 2015, Public Health Services, US Dept of Health and Human Services .All rights reserved.
    Full-text · Article · Nov 2014 · Environmental Health Perspectives
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In order to ensure the welfare of performance horses and riders as well as the integrity of the sport, the use of both therapeutic and illegal agents in horse racing is tightly regulated. While Dehydroepiandrosterone (DHEA) is not specifically banned from administration to racehorses in the United States and no screening limit or threshold concentration exists, the metabolic conversion of DHEA to testosterone make its presence in nutritional supplements a regulatory concern. The recommended regulatory threshold for total testosterone in urine is 55 and 20 ng/mL for mares and geldings, respectively. In plasma, screening and confirmation limits for free testosterone (mares and geldings), of no greater than 0.1 and 0.025 ng/mL, respectively are recommended. DHEA was administered orally, as part of a nutritional supplement, to 8 exercised female thoroughbred horses and plasma and urine samples collected at pre-determined times post administration. Using liquid chromatography-mass spectrometry (LC-MS), plasma and urine samples were analyzed for DHEA, DHEA-sulfate, testosterone, testosterone-sulfate, pregnenolone, androstenedione, and androstenediol. DHEA was rapidly absorbed with maximal plasma concentrations reaching 52.0 ± 43.8 ng/mL and 32.1 ± 12.9 ng/mL for DHEA and DHEA sulfate, respectively. Free testosterone was not detected in plasma or urine samples at any time. Maximum sulfate conjugated testosterone plasma concentrations were 0.98 ± 1.09 ng/mL. Plasma testosterone-sulfate concentrations did not fall below 0.1 ng/mL and urine testosterone-sulfate below 55 ng/mL until 24–36 h post DHEA administration. Urine testosterone sulfate concentrations remained slightly above baseline levels at 48 h for most of the horses studied. Copyright © 2014 John Wiley & Sons, Ltd.
    Preview · Article · Sep 2014 · Drug Testing and Analysis
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cytosolic SULT1A1 participates in the bioconversion of a plethora of endogenous and xenobiotic substances. Genetic variation in this important enzyme such as SNPs can vary by ethnicity and have functional consequences on its activity. Most SULT1A1 genetic variability studies have been centered on the SULT1A1*1/2 SNP. Highlighted here are not only this SNP, but other genetic variants associated with SULT1A1 that could modify drug efficacy and xenobiotic metabolism. Some studies have investigated how differential metabolism of xenobiotic substances influences susceptibility to or protection from cancer in multiple sites. This review will focus primarily on the impact of SULT1A1 genetic variation on the response to anticancer therapeutic agents and subsequently how it relates to environmental and dietary exposure to both cancer-causing and cancer-preventative compounds.
    No preview · Article · Nov 2014 · Pharmacogenomics
Show more