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Toxins 2014, 6(8), 2348-2362; doi:10.3390/toxins6082348
Article

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

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Received: 16 June 2014; in revised form: 28 July 2014 / Accepted: 30 July 2014 / Published: 8 August 2014
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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.
Keywords: Balkan endemic nephropathy; biotransformation; glutathione transferase A1; ochratoxin A; polymorphism Balkan endemic nephropathy; biotransformation; glutathione transferase A1; ochratoxin A; polymorphism
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Reljic, Z.; Zlatovic, M.; Savic-Radojevic, A.; Pekmezovic, T.; Djukanovic, L.; Matic, M.; Pljesa-Ercegovac, M.; Mimic-Oka, J.; Opsenica, D.; Simic, T. 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. Toxins 2014, 6, 2348-2362.

AMA Style

Reljic Z, Zlatovic M, Savic-Radojevic A, Pekmezovic T, Djukanovic L, Matic M, Pljesa-Ercegovac M, Mimic-Oka J, Opsenica D, Simic T. 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. Toxins. 2014; 6(8):2348-2362.

Chicago/Turabian Style

Reljic, Zorica; Zlatovic, Mario; Savic-Radojevic, Ana; Pekmezovic, Tatjana; Djukanovic, Ljubica; Matic, Marija; Pljesa-Ercegovac, Marija; Mimic-Oka, Jasmina; Opsenica, Dejan; Simic, Tatjana. 2014. "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." Toxins 6, no. 8: 2348-2362.



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