Comparative Metabolism Study of Five Protoberberine Alkaloids in Liver Microsomes from Rat, Rhesus Monkey, and Human

Abstract

Protoberberine alkaloids including berberine, palmatine, jatrorrhizine, coptisine, and epiberberine are major components in many medicinal plants. They have been widely used for the treatment of cancer, inflammation, diabetes, depression, hypertension, and various infectious areas. However, the metabolism of five protoberberine alkaloids among different species has not been clarified previously. In order to elaborate on the metabolism of them, a comparative analysis of their metabolic profile in rat, rhesus monkey, and human liver microsomes was carried out using ultrahigh-performance liquid chromatography coupled with a high-resolution linear trap quadrupole-Orbitrap mass spectrometer (UHPLC-electrospray ionization-Orbitrap MS) for the first time. Each metabolite was identified and semiquantified by its accurate mass data and peak area. Fifteen metabolites were characterized based on accurate MS/MS spectra and the proposed MS/MS fragmentation pathways including demethylation, hydroxylation, and methyl reduction. Among them, the content of berberine metabolites in human liver microsomes was similar with those in rhesus monkey liver microsomes, whereas berberine in rat liver microsomes showed no demethylation metabolites and the content of metabolites showed significant differences with that in human liver microsomes. On the contrary, the metabolism of palmatine in rat liver microsomes resembled that in human liver microsomes. The content of jatrorrhizine metabolites presented obvious differences in all species. The HR-ESI-MS/MS fragmentation behavior of protoberberine alkaloids and their metabolic profile in rat, rhesus monkey, and human liver microsomes were investigated for the first time. The results demonstrated that the biotransformation characteristics of protoberberine alkaloids among different species had similarities as well differences that would be beneficial for us to better understand the pharmacological activities of protoberberine alkaloids.

Coptisine Induces Apoptosis in Human Hepatoma Cells Through Activating 67-kDa Laminin Receptor/cGMP Signaling

“…Recent studies showed that some isoquinoline alkaloids and their N-oxides exhibited different pharmacological activities because of a potential structure–activity relationship ( Iizuka et al, 2002 ; Yu et al, 2014 ). Coptisine, one of the isoquinoline alkaloids, has been reported to exhibit an anti-tumor effect on colon and breast cancer, but little is known regarding its effect on liver cancer ( Zhang et al, 2014 ; Li et al, 2017 ). Tao et al reported that the anti-tumor property of coptisine was comparable and even exceeded that of the conventional anti-tumor drugs such as cisplatin and adriamycin, which was similar to the inhibition of the growth of tumor xenografts in a mouse model ( Huang T. et al, 2017 ).…”

Electrochemical microreactor combined with mass spectrometry for online oxidation and real‐time detection of alkaloids

“…To the best of our knowledge, the electrochemical oxidation and determination of four alkaloids in C. chinensis has not been studied so far, and there are no relevant literature records for in vitro metabolism. However, some other conventional metabolic techniques such as liver microsomes (from rat, monkey, and human), rat plasma, metabolism of zebrafish, and human recombinant CYP enzymes have been already appraised for this purpose [25][26][27][28][29][30]. Studies have confirmed that BBR can be absorbed by organisms and metabolized into products in the form of demethylation, reduction, hydroxylation, glucuronidation, and the like.…”

Efficacy and underlying mechanisms of berberine against lipid metabolic diseases: a review

“…Therefore, clinical doses of BBR should be carefully controlled when using it to treat acute hepatitis ( Dai et al, 2018 ). In addition, tandem mass spectrometry revealed that the content of BBR metabolites in human liver microsomes is significantly different from that in rat liver microsomes ( Li et al, 2017 ). Therefore, data related to the rat liver metabolism of BBR should be carefully refer-enced when developing BBR drugs.…”