Is Increased Susceptibility to Balkan Endemic Nephropathy in Carriers of Common GSTA1 (*A/*B) Polymorphism Linked with the Catalytic Role of GSTA1 in Ochratoxin A Biotransformation? Serbian Case Control Study and In Silico Analysis

Abstract

Although recent data suggest aristolochic acid as a putative cause of Balkan endemic nephropathy (BEN), evidence also exists in favor of ochratoxin A (OTA) exposure as risk factor for the disease. The potential role of xenobiotic metabolizing enzymes, such as the glutathione transferases (GSTs), in OTA biotransformation is based on OTA glutathione adducts (OTHQ-SG and OTB-SG) in blood and urine of BEN patients. We aimed to analyze the association between common GSTA1, GSTM1, GSTT1, and GSTP1 polymorphisms and BEN susceptibility, and thereafter performed an in silico simulation of particular GST enzymes potentially involved in OTA transformations. GSTA1, GSTM1, GSTT1 and GSTP1 genotypes were determined in 207 BEN patients and 138 non-BEN healthy individuals from endemic regions by polymerase chain reaction (PCR). Molecular modeling in silico was performed for GSTA1 protein. Among the GST polymorphisms tested, only GSTA1 was significantly associated with a higher risk of BEN. Namely, carriers of the GSTA1*B gene variant, associated with lower transcriptional activation, were at a 1.6-fold higher BEN risk than those carrying the homozygous GSTA1*A/*A genotype (OR = 1.6; p = 0.037). In in silico modeling, we found four structures, two OTB-SG and two OTHQ-SG, bound in a GSTA1 monomer. We found that GSTA1 polymorphism was associated with increased risk of BEN, and suggested, according to the in silico simulation, that GSTA1-1 might be involved in catalyzing the formation of OTHQ-SG and OTB-SG conjugates.

Common Polymorphisms in<i> GSTA1</i>, <i>GSTM1</i> and <i>GSTT1 </i>Are Associated with Susceptibility to Urinary Bladder Cancer in Individuals from Balkan Endemic Nephropathy Areas of Serbia

“…Indeed, our group has showed that GSTT1-active genotype is associated with TCC risk in men exposed to pesticides . Regarding the potential role of GSTT1 in metabolism of OTA and aristolochic acid, the results of our recent investigation did not show involvement of this enzyme in OTA metabolism (Reljic et al 2014), while data on aristolochic-acid metabolism and GSTT1 are lacking. Still, it is noteworthy mentioning that our results on association of GSTT1 polymorphism between risk of TCC bladder cancer and residence in BEN-area are in line with results of Lebrun et al (2006) who pointed out the role of GSTT1 polymorphism in the extent of DNA damage induced by OTA.…”

“…Recently, our group showed that individuals with one or both low-activity GSTA1*B alleles are at 1.6-fold higher risk of BEN than individuals carrying the wild type homozygous GSTA1*A/*A genotype (Reljic et al 2014). The main result obtained from this study pointed out that TCC risk in individuals from BEN areas is modified by GSTA1 gene polymorphism.…”

“…Given a thought that GSTs catalyze some reactions of OTA metabolism, one of the possible causes of BEN, we hypothesized that GST polymorphisms might alter individual susceptibility to bladder cancer in individuals from BENregion. Indeed, our previous results based on in silico simulation suggested that GSTA1 is involved in metabolizing OTA quinone derivatives (Reljic et al 2014). As GSTA1 gene polymorphism results in lowering of enzyme activity, it is reasonable to assume that these individuals will be under both increased oxidative stress and risk of cancer development when exposed to higher concentration of OTA metabolites.…”

“…Certain nephrocarcinogenic compounds, including those associated with BEN, such as OTA, are metabolized by cytosolic glutathione S-transferase (GST) family of enzymes (Tozlovanu et al 2012;Reljic et al 2014). Cytosolic GSTs belong to phase II detoxifying enzymes that protect normal cells by catalyzing conjugation of electrophylic compounds of exogenous and endogenous origin with glutathione (Hayes et al 2005).…”

“…There is evidence on the role of GSTM1 and GSTT1 genetic polymorphisms in the sensitivity of uroepithelial cells to genotoxic OTA effects in vitro (Lebrun et al 2006). Furthermore, there are some data indicating that GSTA1 may catalyze the formation of OTA conjugates (Reljic et al 2014).…”