Sulfotransferase gene copy number variation: pharmacogenetics and function

Abstract

Pharmacogenetics is the study of the role of inheritance in variation to drug response. Drug response phenotypes can vary from adverse drug reactions at one end of the spectrum to equally serious lack of the desired effect of drug therapy at the other. Many of the current important examples of pharmacogenetics involve inherited variation in drug metabolism. Sulfate conjugation catalyzed by cytosolic sulfotransferase (SULT) enzymes, particularly SULT1A1, is a major pathway for drug metabolism in humans. Pharmacogenetic studies of SULT1A1 began over a quarter of a century ago and have advanced from biochemical genetic experiments to include cDNA and gene cloning, gene resequencing, and functional studies of the effects of single nucleotide polymorphisms (SNPs). SNP genotyping, in turn, led to the discovery of functionally important copy number variations (CNVs) in the SULT1A1 gene. This review will briefly describe the evolution of our understanding of SULT1A1 pharmacogenetics and CNV, as well as challenges involved in utilizing both SNP and CNV data in an attempt to predict SULT1A1 function. SULT1A1 represents one example of the potential importance of CNV for the evolving disciplines of pharmacogenetics and pharmacogenomics.

Absorption, Distribution, Metabolism, and Excretion of the Novel Antibacterial Prodrug Tedizolid Phosphate

“…Interestingly, the sex differences were not noted in dog studies, suggesting that unique differences in SULT expression or isoform availability in rodents may account for the sex differences. Variations in SULT isoform, copy number, and polymorphisms have also been described across ethnic backgrounds in humans (Carlini et al, 2001;Nagar et al, 2006;Hildebrandt et al, 2007;Hebbring et al, 2008).…”

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development

“…Several human isoforms with overlapping specificities are responsible for the metabolism of numerous drugs, environmental toxins, and endogenous compounds [10]. Similar to many other substrates [11–13], germline genetic variation in UGT and SULT may impact the interpatient variability in the disposition of ABT-751. In this study, we demonstrate how to perform an optimized pharmacogenetic assessment of a novel anticancer agent during its early phase of development and to describe the pharmacogenetic associations.…”

Copy Number Variation and Warfarin Dosing: Evaluation of CYP2C9 , VKORC1 , CYP4F2 , GGCX and CALU

“…CNVs are heritable duplication and deletion alleles, which can have functional consequences on protein abundance and/or enzyme activity. It is estimated that up to approximately 12% of the human genome harbors CNVs [34], which include several known pharmacogenetic genes: CYP2D6 [42,43], GSTT1 and GSTM1 [44,45], SULT1A1 [46,47] and UGT2B17 [48]. Although one GWAS on warfarin dosing incorporated CNV detection in a subset of their cases [20], the probe density of their genome-wide platform had low resolution for copy number analyses, limiting the ability to detect smaller CNVs that potentially could influence therapeutic warfarin dose requirements.…”