Thus our data demonstrate that polymorphisms of

Thus, our data demonstrate that polymorphisms of GSTP1-1 differentially mediate activation of Prdx6 peroxidase activity, providing a platform to imply that contingent upon their GSTP genotype, individuals will have significant differences in mounting an antioxidant response, particularly affecting protection of cell membranes against lipid peroxidation. Of particular interest, our results indicate that quantitative GSTP1-1 R-115777 inversely correlates with GPx4 levels in MCF-7 cells. This could indicate the presence of a coregulatory mechanism governing expression of Prdx6 and GPx4 in mounting an antioxidant response. This concept is currently under investigation. Polymorphic variants of GSTP will also potentially influence S-glutathionylation of other client proteins' clusters [27]. Moreover, previous studies have suggested that GSTP1 polymorphisms are associated with cancer risk with frequencies of 0.65 (GSTP1-1A), 0.262 (GSTP1-1B), and 0.068 (GSTP1-1C) in Caucasian populations [22], [30]. Such differences will be of importance in the analysis of epidemiological data studying differences in population sensitivities to oxidant-stress-involving procedures.
Acknowledgments This work was supported by grants from the National Institutes of Health (CA08660, CA117259, NCRR P20RR024485–COBRE in Oxidants, Redox Balance and Stress Signaling) and support from the South Carolina Centers of Excellence Program and was conducted in a facility constructed with the support of the National Institutes of Health, Grant C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources. This work was also supported in part by the Drug Metabolism and Clinical Pharmacology Shared Resource, Hollings Cancer Center, Medical University of South Carolina.
Introduction Autism Spectrum Disorder (ASD) affects language development, communication, imagination, and social interactions. Repetitive, stereotyped behaviors are characteristic features of ASD (Rapin, 1997) that manifest in early childhood (Genuis, 2009, Volkmar et al., 2005). The etiology of ASD is believed to be multifactorial (Gardener, Spiegelman, & Buka, 2011), and researchers believe that ASD is caused by interplay among genes (Anderson et al., 2008, Anderson et al., 2009, Ashley-Koch et al., 2007, Bill and Geschwind, 2009, Bowers et al., 2011, Campbell et al., 2008, Kim et al., 2008, Kumar and Christian, 2009, Ma et al., 2005) and between genes and environmental factors (Hallmayer et al., 2011, Herbert, 2010, Landrigan, 2010). Any individual factor in isolation, either genetic or environmental, is usually insufficient to explain the ASD phenotype (James, 2008). Several previous studies have investigated the effect of oxidative stress on neuronal cell death or brain damage (Kern & Jones, 2006), and have linked oxidative stress, the imbalance between levels of reactive oxygen species (ROS), and antioxidant levels in the body with ASD (Chauhan and Chauhan, 2006, James, 2008, Main et al., 2012, McGinnis, 2004). It has also been shown that synthesis of glutathione, the major cellular antioxidant (Coles and Kadlubar, 2003, Maher, 2006), is impacted by factors including genetics, environmental exposures, or methionine metabolism (James, 2008). Levels of glutathione and the ratio of reduced (active) to oxidized (non-active) glutathione were lower in children with ASD compared to children without ASD (James, 2008, James et al., 2004, James et al., 2006), suggesting the involvement of oxidative stress in the disorder. Another study investigated the role of enzymes and metabolites involved in methionine metabolism and found decreased capacity for methylation may contribute to the development of ASD (James et al., 2004). Members of the glutathione-S-transferase (GST) protein family play a major role in defense against oxidative stress by catalyzing the conjugation of glutathione to a variety of electrophilic toxins, which facilitates their excretion (Sharma, Yang, Sharma, Awasthi, & Awasthi, 2004). Some studies reported that mutations and dysfunction in the GST genes could result in oxidative damage (Sharma et al., 2004, Sharma et al., 2010), which may contribute to the development of oxidative stress in children with ASD (Chauhan & Chauhan, 2006). In addition, enzymes generated by GST genes play an important role in detoxification of the products of oxidative stress and heavy metals (Garrecht & Austin, 2011). Several of the GST family subgroup genes, including GST mu 1 (GSTM1), GST pi 1 (GSTP1), and GST theta 1 (GSTT1), are highly polymorphic (Loktionov et al., 2001). Sequence variation in these genes has also been associated with an increased or decreased risk for several cancers and chronic diseases, including colorectal cancer (Loktionov et al., 2001), esophageal cancer (Sharma et al., 2013), renal cell carcinoma (Cheng et al., 2012, Yang et al., 2013), acute leukemia (Ye & Song, 2005), prostate cancer (Harries et al., 1997, Kote-Jarai et al., 2001, Liu et al., 2013, Safarinejad et al., 2011, Taioli et al., 2011, Wei et al., 2013), type-2 diabetes mellitus (Dadbinpour et al., 2013, Ramprasath et al., 2011), asthma (Tamer et al., 2004), and neurodevelopmental disorders such as ASD (Buyske et al., 2006). The variants in GSTM1 and GSTT1 examined here are insertion–deletion polymorphisms, and the homozygous deletions or null genotypes indicate that activities or functionality of these genes are reduced or interrupted completely (Ye, Song, Higgins, Pharoah, & Danesh, 2006).