Značaj genetskog polimorfizma glutation transferaza u nastanku balkanske endemske nefropatije

Abstract

Cilj: Balkanska endemska nefropatija (BEN) je hronična tubulointersticijska bolest, endemski prisutna u određenim seoskim sredinama Srbije, Bosne, Hrvatske, Bugarske i Rumunije. Kao mogući faktori rizika za nastanak BEN, smatraju se izloženost aristolohičnoj kiselini i ohratoksinu A (OTA). Potencijalna uloga enzima koji metabolišu ksenobitike, kao što su glutation transferaze (GST), u metabolizmu OTA zasniva se na prisustvu konjugata OTA sa glutationom u krvi i urinu bolesnika sa BEN. Kako, glutation transferaze imaju potencijal da konjuguju OTA i njegove metabolite, s jedne strane, i smanje količinu slobodnih radikala nastalih u metabolizmu OTA, s druge strane, postoji mogućnost da GST genotipske varijante, udružene sa odsustvom ili nižom enzimskom aktivnošću, mogu da modifikuju individualnu osetljivost za nastanak BEN. Zbog toga, cilj našeg istraživanja je bio da ispita udruženost genetskog polimorfizma GSTA1, GSTM1, GSTT1 i GSTP1 i rizika za nastanak BEN. Metodologija: Sprovedena studija slučajeva i kontrola je obuhvatala 207 bolesnika sa BEN i 138 zdravih osoba, stanovnika endemskih naselja sa negativnom sa BEN porodičnom anamnezom. Svi učesnici studije su informisani o ciljevima i očekivanim ishodima studije i od njih je dobijen pisani pristanak. Protokol studije je odobrio Etički komitet Medicinskog fakulteta (Odluka број 29/VI-13), i istraživanje je sprovedeno u skladu sa Helsinškom deklaracijom (revidiranom 2000. godine)...

Objective: Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease, recognized as endemic in certain rural areas of Serbia, Bosnia, Croatia, Bulgaria, and Romania. Despite extensive research, its etiology is still unknown. Although recent data suggest aristolochic acid as a putative cause of 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 the presence of OTA glutathione adducts in blood and urine of BEN patients. Since, glutathione transferase have potential to conjugate OTA and its metabolites on one hand, and reduce free radicals that originate from OTA metabolites on the other, it is possible that the GST genotype variations, with a consequent absent or lower enzyme activities, may modify individual susceptibility to BEN. Therefore, the aim of our study was to investigate the association between common GSTA1, GSTM1, GSTT1 and GSTP1 polymorphisms and BEN susceptibility. Methodology: The conduced, case-control study comprised 207 BEN patients and 138 healthy individuals, residents of endemic settlements with a negative family BEN history. All the participants provided written informed consent. This study protocol was approved by the Institutional Review Board (permission number 29/VI-13), and the research was carried out in compliance with the Helsinki Declaration (as revised in 2000). GSTA1, GSTM1, GSTT1 and GSTP1 genotypes were determined in 207 BEN patients and 138 non-BEN healthy individuals, from endemic regions...