Xanthotoxin (XTT) is a biologically active furanocoumarin widely present in foods and plants. The present study is designed to systematically investigate the enzymatic interaction of XTT with CYP1A2, along with pharmacokinetic alteration of tacrine resulting from the co-administration of XTT. The results showed that XTT induced a time-, concentration-, and NADPH-dependent inhibition of CYP1A2, and the inhibition was irreversible. Coincubation of glutathione (GSH) and catalase/superoxide dismutase was unable to prevent enzyme inactivation. Nevertheless, competitive inhibitor fluvoxamine exhibited a concentration-dependent protective effect against the XTT-induced CYP1A2 inactivation. A GSH trapping experiment provided strong evidence for the production of epoxide or/and γ-ketoenal intermediates resulting from the metabolic activation of XTT. Furthermore, pretreatment of rats with XTT was found to significantly increase the C max and area under the curve of plasma tacrine relative to those of tacrine administration alone.
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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