Retrorsine (RTS) is a toxic retronecine‐type pyrrolizidine alkaloid, which is widely distributed. The purpose of this study was to develop a high‐performance liquid chromatography–tandem mass spectrometric (LC–MS/MS) method for serum RTS determination in mice. Serum samples were deproteinated by acetonitrile, separated on a C18‐PFP column and delivered at 0.8 ml/min with an eluting system composed of water containing 0.1% (v/v) formic acid and acetonitrile containing 0.1% (v/v) formic acid as mobile phases. RTS and the internal standard S‐hexylglutathione (H‐GSH) were quantitatively monitored with precursor‐to‐product transitions of m/z 352.1 → 120.1 and m/z 392.2 → 246.3, respectively. The method showed excellent linearity over the concentration range 0.05–50 μg/ml, with correlation coefficient r2 = 0.9992. The extraction recovery was >86.34%, and the matrix effect was not significant. Inter‐ and intra‐day precisions (RSD) were <4.99%. The validated LC–MS/MS method was successfully applied to study the toxicokinetic profiles of serum RTS in mice after intravenous, oral administration and co‐treated with ketoconazole, which showed that RTS displayed a long half‐life (~11.05 h) and good bioavailability (81.80%). Co‐administration of ketoconazole (KTZ) increased the peak serum concentration and area under the concentration–time curve and decreased the clearance and mean residence time. Summing up, a new standardized method was established for quantitative determination of RTS in sera.
Bletilla striata is consumed as
food and herbal medicine. Militarine (MLT) is a major ingredient in B. striata. Previous studies demonstrated that MLT
showed teratogenic toxicity to zebrafish embryos. The present study
aimed to identify reactive metabolites possibly involved in the cytotoxicity
of MLT and determine the metabolic pathways involved. MLT was found
to be hydrolyzed to p-hydroxybenzyl alcohol (HBA)
by β-glucosidase and esterases. The resulting HBA further underwent
spontaneous dehydration to form quinone methide. HBA was also metabolized
to the corresponding sulfate, followed by departure of the sulfate
to generate a quinone methide. The resultant quinone methide reacted
with hepatic glutathione (GSH) and protein to form the corresponding
GSH conjugate and protein adduction. Additionally, inhibition of sulfotransferases
(SULTs) attenuated the susceptibility of hepatocytes to the toxicity
of MLT. This study provides that the hydrolytic enzymes β-glucosidase,
esterases, and SULTs participate in the metabolic activation of MLT.
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