Metabolic Profile, Bioavailability and Toxicokinetics of Zearalenone-14-Glucoside in Rats after Oral and Intravenous Administration by Liquid Chromatography High-Resolution Mass Spectrometry and Tandem Mass Spectrometry.

Feifei Sun,Yi Li,Haiguang Tan,Huiyan Zhang,Yanshen Li,Sarah De Saeger,Zhenghua Rao,Marthe De Boevre,Shupeng Yang,Jinhui Zhou

doi:10.3390/ijms20215473

Abstract

Zearalenone-14-glucoside (ZEN-14G), a key modified mycotoxin, has attracted a great deal of attention due to the possible conversion to its free form of zearalenone (ZEN) exerting toxicity. In this study, the toxicokinetics of ZEN-14G were investigated in rats after oral and intravenous administration. The plasma concentrations of ZEN-14G and its major five metabolites were quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The data were analyzed via non-compartmental analysis using software WinNonlin 6.3. The results indicated that ZEN-14G was rapidly hydrolyzed into ZEN in vivo. In addition, the major parameters of ZEN-14G following intravenous administration were: area under the plasma concentration–time curve (AUC), 1.80 h·ng/mL; the apparent volume of distribution (VZ), 7.25 L/kg; and total body clearance (CL), 5.02 mL/h/kg, respectively. After oral administration, the typical parameters were: AUC, 0.16 h·ng/mL; VZ, 6.24 mL/kg; and CL, 4.50 mL/h/kg, respectively. The absolute oral bioavailability of ZEN-14G in rats was about 9%, since low levels of ZEN-14G were detected in plasma, which might be attributed to its extensive metabolism. Therefore, liquid chromatography high-resolution mass spectrometry (LC-HRMS) was adopted to clarify the metabolic profile of ZEN-14G in rats’ plasma. As a result, eight metabolites were identified in which ZEN-14-glucuronic acid (ZEN-14GlcA) had a large yield from the first time-point and continued accumulating after oral administration, indicating that ZEN-14-glucuronic acid could serve a potential biomarker of ZEN-14G. The obtained outcomes would prompt the accurate safety evaluation of ZEN-14G.

Highlights

Zearalenone (ZEN), produced by the filamentous Fusarium fungi, is one of the most frequently occurring Fusarium mycotoxins [1,2]
The absolute oral bioavailability of ZEN-14G in rats was about 9%, since low levels of ZEN-14G were detected in plasma, which might be attributed to its extensive metabolism
High-resolution mass spectrometry (HRMS) and triple quadrupole coupled to mass spectrometry (MS/MS) have been widely used in various fields, including metabolism, environmental toxicity, and safety evaluation

Summary

Introduction

Zearalenone (ZEN), produced by the filamentous Fusarium fungi, is one of the most frequently occurring Fusarium mycotoxins [1,2]. ZEN can react with estrogenic receptors, exhibiting estrogen-like activity [3]. The modified forms of mycotoxins have recently attracted considerable attention [4,5]. Food and feed contaminated with modified mycotoxins such as ZEN-14-glucoside (ZEN-14G) or deoxynivalenol-3-β-D-glucoside (DON-3G) could result in potential underestimation of the exposure [4,6]. The European Commission stated that it is appropriate to evaluate the exposure to modified forms of various toxins in addition to the parent compounds [7], since the modified forms might be hydrolyzed into the parent toxins, exerting toxicity [8,9]. The estrogenic potency of ZEN-14G is comparable to that of ZEN [7]

Methods

Results

Conclusion