Glutathione Conjugates of Ochratoxin a as Biomarkers of Exposure / Glutationski Konjugati Okratoksina A Kao Biomarkeri Izloženosti

Abstract

In the present study the photoreactivity of the fungal carcinogen ochratoxin A (OTA) has been utilised to generate authentic samples of reduced glutathione (GSH) and N-acetylcysteine (NAC) conjugates of the parent toxin. These conjugates, along with the nontoxic OTα, which is generated through hydrolysis of the amide bond of OTA by carboxypeptidase A, were utilised as biomarkers to study the metabolism of OTA in the liver and kidney of male and female Dark Agouti rats. Male rats are more susceptible than female rats to OTA carcinogenesis with the kidney being the target organ. Our studies show that the distribution of OTA in male and female rat kidney is not signifi cantly different. However, the extent of OTA metabolism was greater in male than female rats. Much higher levels of OTα were detected in the liver compared to the kidney, and formation of OTα is a detoxifi cation pathway for OTA. These fi ndings suggest that differences in metabolism between male and female rats could provide an explanation for the higher sensitivity of male rats to OTA toxicity.

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

“…Among OTA metabolites, OTHQ exerts strong pro-oxidant activity. Like other hydroquinones, OTHQ undergoes oxidation to generate superoxide and the quinone electrophile OTQ [10]. In the human renal proximal tubular epithelial cell line (HK-2), it was found that OTA treatment led to the release of reactive oxygen species and the increase of 8-hydroxydeoxyguanosine, an important biomarker of oxidative DNA damage [33].…”

“…Existence of this pathway in humans was supported by evidence of OTHQ-SG presence in blood and urine samples of BEN patients. Furthermore, in addition to OTHQ-SG, very recently the presence of OTB-SG (Chart 2) conjugates has also been shown in this biological material [7,10]. …”

Degradation of ochratoxin A byBacillus amyloliquefaciensASAG1

“…Research conducted by Xiao et al demonstrated that OTA was cleaved into the non-toxic ochratoxin α (OTα) and L-phenylalanine (Phe) by carboxypeptidase (1995). Moreover, the metabolism of OTA, along with that of the nontoxic OTα, hydrolysed by carboxypeptidase, was measured, and the kinetic data on OTA were clarified (Stander et al 2001;Tozlovanu et al 2012). It can be inferred that the derived metabolites of OTA were hydrolysed into OTα by carboxypeptidase produced by ASAG1.…”

Toxicity of Ochratoxin A and Its Modulation by Antioxidants: A Review

“…Obtained data suggest that OTA is not acting as a direct genotoxic carcinogen and that oxidative stress is implicated in the genotoxicity and cytotoxicity observed in these human renal cells. In the same cell line (HK2), as well as in rat liver and kidney, covalent DNA adducts have been observed and related to OTA biotransformation [17,108]. Although, oral exposure to mycotoxins is the common route, it has been suggested by WHO that because of the employment of manual labor during the pre- and post-harvest stages of agriculture, dermal exposure to these chemicals may also occur [109].…”

“…[108] reported that OTA, as well as electrophiles generated from its metabolism react with reduced glutathione (GSH) to produce GSH-conjugates. In kidney, OTB-GSH is the major metabolite.…”