title: 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.
authors.affiliation: Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. panlabkv@yahoo.com.
authors.forename: Zorica
authors.initials: Z
authors.lastname: Reljic
authors.affiliation: Faculty of Chemistry, University of Belgrade, 11000 Belgrade, Serbia. mario@chem.bg.ac.rs.
authors.forename: Mario
authors.initials: M
authors.lastname: Zlatovic
authors.affiliation: Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. asradojevic@tehnicom.net.
authors.forename: Ana
authors.initials: A
authors.lastname: Savic-Radojevic
authors.affiliation: Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. pekmezovic@sezampro.rs.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Pekmezovic
authors.affiliation: Clinic of Nephrology, Clinical Center of Serbia, 11000 Belgrade, Serbia. ljubicadjukanovic@yahoo.com.
authors.forename: Ljubica
authors.initials: L
authors.lastname: Djukanovic
authors.affiliation: Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. marija_opacic@yahoo.com.
authors.forename: Marija
authors.initials: M
authors.lastname: Matic
authors.affiliation: Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. marijaercegovac@med.bg.ac.rs.
authors.forename: Marija
authors.initials: M
authors.lastname: Pljesa-Ercegovac
authors.affiliation: Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. okasn@rcub.bg.ac.rs.
authors.forename: Jasmina
authors.initials: J
authors.lastname: Mimic-Oka
authors.affiliation: Institute of Chemistry, Technology, and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia. dopsen@chem.bg.ac.rs.
authors.forename: Dejan
authors.initials: D
authors.lastname: Opsenica
authors.affiliation: Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia. tatjanasimic@med.bg.ac.rs.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Simic
mesh_terms: D000368:Aged; D001449:Balkan Nephropathy / Q000453:epidemiology / Q000235:genetics*; D001711:Biotransformation; D016022:Case-Control Studies; D002384:Catalysis; D003198:Computer Simulation; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009793:Ochratoxins / Q000378:metabolism; D011110:Polymorphism, Genetic; D055771:Serbia / Q000453:epidemiology
chemical_list: D009793:Ochratoxins; C025589:ochratoxin A; C484555:GSTA1 protein, human; D005982:Glutathione Transferase
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