Characterization of in vitro metabolites of cudratricusxanthone A in human liver microsomes

Abstract

Cudratricusxanthone A (CTXA), isolated from the roots of Cudrania tricuspidata, exhibits several biological activities; however, metabolic biotransformation was not investigated. Therefore, metabolites of CTXA were investigated and the major metabolic enzymes engaged in human liver microsomes (HLMs) were characterized using liquid chromatography-tandem mass spectrometry (LC-MS/MS). CTXA was incubated with HLMs or human recombinant CYPs and UGTs, and analysed by an LC-MS/MS equipped electrospray ionization (ESI) to qualify and quantify its metabolites. In total, eight metabolites were identified: M1-M4 were identified as mono-hydroxylated metabolites during Phase I, and M5-M8 were identified as O-glucuronidated metabolites during Phase II in HLMs. Moreover, these metabolite structures and a metabolic pathway were identified by elucidation of MS(n) fragments and formation by human recombinant enzymes. M1 was formed by CYP2D6, and M2-M4 were generated by CYP1A2 and CYP3A4. M5-M8 were mainly formed by UGT1A1, respectively. While investigating the biotransformation of CTXA, eight metabolites of CTXA were identified by CYPs and UGTs; these data will be valuable for understanding the in vivo metabolism of CTXA.

Cudrania tricuspidata: an updated review on ethnomedicine, phytochemistry and pharmacology

“…The in vitro metabolic proling of CTXA in human liver microsomes has been recently investigated, which revealed that eight identied metabolites of CTXA were involved with cytochrome P450 enzymes (CYPs) and uridine 5 0 -diphospho-glucuronosyltransferase enzymes (UGTs). 138 In a follow-up study, CTXA has been demonstrated to exhibit reversible competitive inhibition of CYP1A2 and CYP2C9 and non-competitive inhibition of CYP2C8 in human liver microsomes, which has begun to shed light on the in vivo metabolism of CTXA. 139 Cudratricusxanthone B, as another example, has also been investigated for its pharmacokinetics by a fast and sensitive HPLC-MS/ MS method, but its oral bioavailability (OB) remains unclear and merits future investigation.…”

Identification of suberosin metabolites in human liver microsomes by high‐performance liquid chromatography combined with high‐resolution quadrupole–orbitrap mass spectrometer

“…Despite the hydroxylation of the same pentane moiety, the related CYPs differed for each compound. Here CYP1A2, CYP2A6, and CYP2B6 were involved in the metabolism of suberosin, whereas CYP2B6 and CYP2D6 were involved in the metabolism of CTXA 32 . Moreover, glycyrol, also predominantly metabolized by CYP1A2, and osthenol was hydroxylated at the pentane moiety by CYP 1A1 and CYP2D6 33,34 .…”

“…In addition to the current research, the CYPs are described as involved in the metabolites of compounds possessing a C5 isoprene (dimethylallyl) moiety in their structure and are bioactive molecules from plants that have been consumed as foods or supplements. [32][33][34] Hydroxylation of the pentane moiety has been identified as the primary phase I metabolic pathway of prenylflavonoids in HLMs, with cudratricusxanthone A (CTXA), glycyrol, and osthenol, including suberosin. Despite the hydroxylation of the same pentane moiety, the related CYPs differed for each compound.…”

“…Here CYP1A2, CYP2A6, and CYP2B6 were involved in the metabolism of suberosin, whereas CYP2B6 and CYP2D6 were involved in the metabolism of CTXA. 32 Moreover, glycyrol, also predominantly metabolized by CYP1A2, and osthenol was hydroxylated at the pentane moiety by CYP 1A1 and CYP2D6. 33,34 Thus, it can be concluded that the enzymes involved in the metabolism of the pentane moiety of prenylflavonoids are determined by the overall flavonoid structure rather than by the pentane moiety.…”

PINK1/Parkin-mediated mitophagy inhibits warangalone-induced mitochondrial apoptosis in breast cancer cells

“…Studies have reported that bioactive components extracted from Carr . exhibit hepatoprotective [ 12 ], anti-oxidant [ 13 ] and anti-cancer effects [ 14 ]. However, there has been little study of the bioactive components of the fruit of Cudrania tricuspidata .…”