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

Zorica Reljic¹  Mario Zlatovic²  Ana Savic-Radojevic¹  Tatjana Pekmezovic³  Ljubica Djukanovic⁵  Marija Matic¹  Marija Pljesa-Ercegovac¹  Jasmina Mimic-Oka¹  Dejan Opsenica⁴ 

[1] Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; E-Mails:;Faculty of Chemistry, University of Belgrade, 11000 Belgrade, Serbia; E-Mail:;Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia; E-Mail:;Institute of Chemistry, Technology, and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia;Clinic of Nephrology, Clinical Center of Serbia, 11000 Belgrade, Serbia; E-Mail:

关键词: Balkan endemic nephropathy;    biotransformation;    glutathione transferase A1;    ochratoxin A;    polymorphism;   

DOI  :  10.3390/toxins6082348

来源: mdpi

【 摘 要 】

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, GSTT1and 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*Bgene 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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.