Demethylation of neferine in human liver microsomes and formation of quinone methide metabolites mediated by CYP3A4 accentuates its cytotoxicity

Shen, Qi; Zuo, Minjuan; Ma, Li; Wang, Lu; Jiang, Huidi; Zhou, Quan; Zhou, Hui; Yu, Lushan; Zeng, Su

doi:10.1016/j.cbi.2014.10.014

Cited by 17 publications

(8 citation statements)

References 27 publications

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“…Based on high-performance liquid chromatography and data-dependent electrospray ionization tandem mass spectrometry, Zhou et al discovered three newphase I metabolites in the liver microsomes of beagle dogs, namely, 2-N-desmethylisoliensinine, 2′-N-desmethylisoliensinine, and 2′-N-6-O-didesmethylisoliensinine, indicating that isoliensinine was mainly metabolized in the liver through N-demethylation and O-demethylation (Zhou et al, 2012). It has been reported that neferine is mainly metabolized by CYP450 enzymes, including CYP3A, CYP2B, and CYP2D6, so they also assumed that isoliensinine was metabolized by CYP450 enzyme systems, but the specific enzyme involved in this process was not clear (Huang et al, 2007;Shen et al, 2014).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Isoliensinine: A Natural Compound with “Drug-Like” Potential

Cheng

Zhou

et al. 2021

Front. Pharmacol.

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Isoliensinine, a bisbenzylisoquinoline alkaloid isolated from Nelumbo nucifera Gaertn, exerts a variety of beneficial effects, such as antitumor, cardioprotective, antioxidant, antidepressant, and anti-HIV effects, and ameliorates T2DM with hyperlipidemia and Alzheimer’s disease. In this article, the recent literature on isoliensinine, including its pharmacology, pharmacokinetics, and synthesis and extraction, is summarized. Moreover, possible future prospects and research directions are also discussed. Studies on isoliensinine were found by searching a combination of keywords including “pharmacology,” “pharmacokinetics,” and “synthesis and extraction” in the main databases, including PubMed, Google Scholar, Web of Science, NCBI, and Wan Fang. Many studies have pointed out that a major limitation of isoliensinine is its poor solubility in aqueous media. Considering its advantages and limitations, isoliensinine can be used as a lead compound to develop novel efficient and low-toxicity derivatives. The available literature indicates that isoliensinine displays “drug-like” potential. Additionally, there are many related issues and novel mechanisms that need to be explored.

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Section: Pharmacokineticsmentioning

confidence: 99%

Isoliensinine: A Natural Compound with “Drug-Like” Potential

Cheng

Zhou

et al. 2021

Front. Pharmacol.

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“…Metabolic activation of tetrandrine can lead to pulmonary toxicity toward CD-1 mice ( Jin et al, 2011 ), and CYP3A5 mediated bioactivation was also closely associated with cytotoxicity of tetrandrine ( Tian et al, 2016 ). CYP3A4 predominantly catalyzed the formation of neferine-GSH conjugates, and GSH depletion significantly aggravated neferine-induced cytotoxicity ( Shen et al, 2014 ). Taken together, para- methylene phenol is key toxic structural alerts of bisbenzylisoquinoline alkaloids , and activated para -quinone methides bio transforming from para - methylene phenol is a pivotal step.…”

Section: Cyp450s Mediated Metabolic Activation Of Natural Products Leading To Toxicitymentioning

confidence: 99%

Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities

Wang

Xia

et al. 2021

Front. Pharmacol.

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Currently, herbal and dietary supplements have been widely applied to prevent and treat various diseases. However, the potential toxicities and adverse reactions of herbal and dietary supplements have been increasingly reported, and have gradually attracted widespread attention from clinical pharmacists and physicians. Metabolic activation of specific natural products from herbal and dietary supplements is mediated by hepatic cytochrome P450 or intestinal bacteria, and generates chemical reactive/toxic metabolites that bind to cellular reduced glutathione or macromolecules, and form reactive metabolites-glutathione/protein/DNA adducts, and these protein/DNA adducts can result in toxicities. The present review focuses on the relation between metabolic activation and toxicities of natural products, and provides updated, comprehensive and critical comment on the toxic mechanisms of reactive metabolites. The key inductive role of metabolic activation in toxicity is highlighted, and frequently toxic functional groups of toxic natural products were summarized. The biotransformation of drug cytochrome P450 or intestinal bacteria involved in metabolic activation were clarified, the reactive metabolites-protein adducts were selected as biomarkers for predicting toxicity. And finally, further perspectives between metabolic activation and toxicities of natural products from herbal and dietary supplements are discussed, to provide a reference for the reasonable and safe usage of herbal and dietary supplements.

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“…Both CYP3A and CYP2B are thought to be responsible for the metabolism of neferine, with CYP3A playing a major role (Jiang, Liang, and Xiong 2006). In human liver microsomes, CYP3A, 2C8, and 2D6 were found to catalyse N-and O-demethylation reactions, converting neferine to liensinine, isoliensinine, and other demethylated metabolites (Huang et al 2007;Shen et al 2014). Another investigation on higenamine in human liver microsomes showed that uridine diphosphate glucuronosyltransferase (UGT)1A9 is the major isoenzyme that regulates the glucuronidation of alkaloids (Liang et al 2017).…”

Section: Metabolismmentioning

confidence: 99%

Alkaloids from lotus (Nelumbo nucifera): recent advances in biosynthesis, pharmacokinetics, bioactivity, safety, and industrial applications

Wang

et al. 2021

Critical Reviews in Food Science and Nutrition

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Different parts of lotus (Nelumbo nucifera Gaertn.) including the seeds, rhizomes, leaves, and flowers, are used for medicinal purposes with health promoting and illness preventing benefits. The presence of active chemicals such as alkaloids, phenolic acids, flavonoids, and terpenoids (particularly alkaloids) may account for this plant's pharmacological effects. In this review, we provide a comprehensive overview and summarize up-to-date research on the biosynthesis, pharmacokinetics, and bioactivity of lotus alkaloids as well as their safety. Moreover, the potential uses of lotus alkaloids in the food, pharmaceutical, and cosmetic sectors are explored.Current evidence shows that alkaloids, mainly consisting of aporphines, 1benzylisoquinolines, and bisbenzylisoquinolines, are present in different parts of lotus.The bioavailability of these alkaloids is relatively low in vivo but can be enhanced by technological modification using nanoliposomes, liposomes, microcapsules, and emulsions. Available data highlights their therapeutic and preventive effects on obesity, diabetes, neurodegeneration, cancer, cardiovascular disease, etc. Additionally, industrial applications of lotus alkaloids include their use as food, medical, and cosmetic ingredients in tea, other beverages, and healthcare products; as lipidlowering, anticancer, and antipsychotic drugs; and in facial masks, toothpastes, and shower gels. However, their clinical efficacy and safety remains unclear; hence, larger and longer human trials are needed to achieve their safe and effective use with minimal side effects.

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Demethylation of neferine in human liver microsomes and formation of quinone methide metabolites mediated by CYP3A4 accentuates its cytotoxicity

Cited by 17 publications

References 27 publications

Isoliensinine: A Natural Compound with “Drug-Like” Potential

Isoliensinine: A Natural Compound with “Drug-Like” Potential

Metabolic Activation of the Toxic Natural Products From Herbal and Dietary Supplements Leading to Toxicities

Alkaloids from lotus (Nelumbo nucifera): recent advances in biosynthesis, pharmacokinetics, bioactivity, safety, and industrial applications

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