Tissue distribution, excretion, and metabolism of 2,6-di-tert-butyl-hydroxytoluene in mice

Abstract

As one typical synthetic phenolic antioxidant, 2,6-di-tert-butyl-hydroxytoluene (BHT) has been widely adopted in food and other human products, and considered as an emerging contaminant due to its toxic effects. Understanding bioaccumulation and metabolism of BHT is crucial to evaluate its environmental fate and toxicity. In this study, the tissue distribution, excretion, and metabolism of BHT in mice were investigated. It was shown that BHT was prone to be accumulated in metabolism-related organs (i.e., liver and kidney) with AUC_{0-120 h} (area under the concentration-time curve from 0 to 120 h) values of 206 h·μg/g in liver and 162 h·μg/g in kidney. For metabolites, 2,6-di-tert-butyl-4-hydroxy-4-methyl-2,5-cyclohexadione (BHT-quinol) was preferentially accumulated in liver, while 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH) was the major metabolite in excreta. The major excretion of BHT and metabolites was through feces with a value of 25.1 ± 0.16% of the initial dose compared with urine of 1.27 ± 0.05%. The possible metabolic pathways of BHT were elucidated as the oxidation of the para-methyl, tert-butyl groups, and aromatic ring based on the known and identified unknown metabolites by HPLC-Q-TOF-MS/MS. The preferred accumulation of BHT and metabolites in liver implies their potential hepatotoxicity. Results here also suggested that considering the distribution and excretion of metabolites can better assess BHT's fate and risk in mammals.

Keywords: Bioaccumulation; Metabolic pathways; Metabolites; Synthetic phenolic antioxidants.