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

نویسندگان

  • Zorica Reljic
  • Mario Zlatovic
  • Ana Savic-Radojevic
  • Tatjana Pekmezovic
  • Ljubica Djukanovic
  • Marija Matic
  • Marija Pljesa-Ercegovac
  • Jasmina Mimic-Oka
  • Dejan Opsenica
  • Tatjana Simic
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Polymorphic expression of glutathione transferases A1, M1, P1 and T1 in epithelial ovarian cancer: a Serbian case-control study.

PURPOSE Since several studies have proposed that epithelial ovarian cancer should not be considered as a single disease entity and that it results from an accumulation of genetic changes, we aimed to assess the polymorphic expression of major cytosolic glutathione S-transferases (GSTM1, T1, A1 and P1) with respect to ovarian cancer susceptibility and aggressiveness. METHODS This case-control ...

متن کامل

Role of exposure analysis in solving the mystery of Balkan endemic nephropathy.

We evaluated the role of exposure analysis in assessing whether ochratoxin A or aristolochic acid are the agents responsible for causing Balkan endemic nephropathy. We constructed a framework for exposure analysis using the lessons learned from the study of endemic goiter within the context of an accepted general model. We used this framework to develop an exposure analysis model for Balkan end...

متن کامل

GSTA1, GSTM1, GSTP1 and GSTT1 polymorphisms in progressive myoclonus epilepsy: A Serbian case–control study

PURPOSE Oxidative stress is recognized as an important factor in progressive myoclonus epilepsy (PME). Genetic polymorphism of glutathione S-transferases (GSTs), which are involved in both protection from oxidative damage and detoxification, might alter the capacity for protecting tissues from exogenous and endogenous oxidants. We aimed to assess a possible association between GST polymorphism ...

متن کامل

Polymorphisms and allele frequencies of glutathione S-transferases A1 and P1 genes in the Polish population.

Glutathione S-transferases (GST) A1 and P1 are crucial enzymes involved in the biotransformation of drugs, carcinogens, and toxins, and their activity may influence drug response, susceptibility to diseases, and carcinogenesis. The genes encoding these enzymes, GSTA1 and GSTP1, have been examined in many studies because of their genetic variability, which may affect enzymatic activity. The goal...

متن کامل

بررسی ارتباط پلی‌مورفیسم C677T ژن متیلن تتراهیدروفولات ردکتاز با نفروپاتی دیابتی

Background: Diabetic Nephropathy is one of the main microvascular complications of diabetic mellitus. Methylenetetrahydrofolate Reductase (MTHFR) is one of the candidate genes of diabetic nephropathy. MTHFR (C677T) polymorphism reduces catalytic activity of MTHFR and leads to increase level of plasma homocysteine. The aim of this study was to evaluate the association of C677T polymorphism with ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 6  شماره 

صفحات  -

تاریخ انتشار 2014