Mechanistic Study of Xanthotoxin-Mediated Inactivation of CYP1A2 and Related Drug–Drug Interaction with Tacrine

Abstract

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.

A pragmatic perspective article: synergistic photocatalytic–photothermal effect with its practical applications and future prospects

“…It is urgent to explore effective antibacterials. 40,41 At present, various mechanisms of photocatalysis sterilization are widely accepted. These include that ROS destroy the bacterial membrane and prevent normal metabolism and gene expression (Fig.…”

Chemical nature of metabolic activation of natural products in traditional Chinese medicines possibly associated with toxicities

“…Conversely, certain furanoterpenoids act as mechanism-based inactivators, producing reactive cis -enedial intermediates that can react with moieties in the active site of the enzyme, resulting in the irreversible inactivation of host P450s. For instance, xanthotoxin (methoxsalen, a biologically active furanocoumarin widely present in foods and plants) and bergamottin (a major furanocoumarin constituent of grapefruit) can be characterized as mechanism-based inactivators of CYP1A2 and CYP2C9, respectively, acting via the formation of an epoxide and/or γ -ketoenal reactive intermediates [67,68] .…”

Regulation of band gap and localized surface plasmon resonance by loading Au nanorods on violet phosphene nanosheets for photodynamic/photothermal synergistic anti-infective therapy

“…[39][40][41] However, the rapid photo-induced recombination of photoexcited electron-hole pairs and the low absorption of light impose limitations on the generation of ROS, which is closely associated with antibacterial efficiency. 42,43 To overcome these limitations, a strategy is proposed of loading the VPNSs with metal nanoparticles, which can inhibit the recombination of free charges by accelerating the separation and transport of photogenerated electron-hole pairs to promote increased ROS production. [44][45][46] In particular, VPNSs have a high specific surface area and folded structure, which provide a favorable substrate for metal loading.…”