CYP450 1A2 and multiple UGT1A isoforms are responsible for jatrorrhizine metabolism in human liver microsomes

Zhou, Hui; Shi, Rong; Ma, Bing-Liang; Ma, Yueming; Wang, Changhong; Wu, Di; Wang, Xinhong; Cheng, Ni

doi:10.1002/bdd.1835

Cited by 21 publications

(9 citation statements)

References 16 publications

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“…Female SD rats were orally administered pure berberine (90 mg/kg), and these AUC 0-36 and C max values were 88.8 ng/ml*h and 29.2 ng/ml, respectively, while the AUC 0-24 and C max in our study were 121.57 ng/ ml*h and 148.77 ng/ml, respectively, when the female rats were administered 58.92 mg/kg berberine in TAZF. Berberine and other alkaloids, including jatrorrhizine and palmatine, can be metabolized by CYP3A4, CYP1A2 and CYP2D6 [27][28][29][30]. These enzymes can also be inhibited by epiberberine and berberine [31][32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Toxicity and toxicokinetics of the ethanol extract of Zuojin formula

Wang

Zhang

Liu

et al. 2022

BMC Complement Med Ther

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Background Zuojin formula, a traditional Chinese medicine, comprises Coptis chinensis and Evodia rutaecarpa. In our previous study, the total alkaloid extract from Zuojin formula (TAZF) showed potent and improved efficacy. However, its safety and toxicokinetics remain unknown. The objective of this study was to evaluate the safety of repeated administrations of TAZF and investigate the internal exposure of the main components and its relationship with toxic symptoms. Methods Sprague–Dawley rats were orally administered TAZF at 0.4, 1.2 and 3.7 g/kg for 28 days, which was followed by a 14-day recovery period. The toxic effects were evaluated weekly by assessing body weight changes, food intake, blood biochemistry and haematological indices, organ weights and histological changes. A total of eight components were detected, including berberine, coptisine, epiberberine, palmatine, jatrorrhizine, columbamine, evodiamine, and rutaecarpine. The toxicokinetic profiles of the eight components were investigated after single and repeated administrations. Linear mixed effect models were applied to analyse the associations between internal exposure and toxic symptoms. Network pharmacology analysis was applied to explore the potential toxic mechanisms. Results Compared with the vehicle group, the rats in the low- and medium-dose groups did not show noticeable abnormal changes, while rats in the high-dose group exhibited inhibition of weight gain, a slight reduction in food consumption, abdominal bloating and atrophy of the splenic white pulp during drug administration. The concentration of berberine in plasma was the highest among all compounds. Epiberberine was found to be associated with the inhibition of weight gain. Network pharmacology analysis suggested that the alkaloids might cause abdominal bloating by affecting the proliferation of smooth muscle cells. The benchmark dose lower confidence limits (based on body weight inhibition) of TAZF were 1.27 g/kg (male) and 1.91 g/kg (female). Conclusions TAZF has no notable liver or kidney toxicity but carries risks of gastrointestinal and immune toxicity at high doses. Alkaloids from Coptis chinensis are the main plasma components related to the toxic effects of TAZF.

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Section: Discussionmentioning

confidence: 99%

Toxicity and toxicokinetics of the ethanol extract of Zuojin formula

Wang

Zhang

Liu

et al. 2022

BMC Complement Med Ther

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“…Additionally, seven phase I metabolites of jatrorrhizine after demethylation, dehydrogenation and dihydroxylation, and eleven phase II metabolites including glucuronide and methyl conjugates were detected in rat urine ( Han et al, 2006 ). Cytochrome P450 and UDP-glucuronosyltransferase enzymes are responsible for the metabolism of jatrorrhizine in human liver microsomes, including CYP1A2 and multiple UGT1A isoforms (UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9 and UGT1A10) ( Zhou et al, 2013 ). CYP3A1/2 and CYP2D2 were also involved in demethylation of jatrorrhizine and UGT1A1 and UGT 1A3 were associated with glucuronidation in rat liver microsomes ( Shi et al, 2012 ).…”

Section: Pharmacokinetics Of Jatrorrhizinementioning

confidence: 99%

Jatrorrhizine: A Review of Sources, Pharmacology, Pharmacokinetics and Toxicity

Zhong

Chen

et al. 2022

Front. Pharmacol.

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Jatrorrhizine, an isoquinoline alkaloid, is a bioactive metabolite in common medicinal plants, such as Berberis vernae Schneid., Tinospora sagittata (Oliv.) Gagnep. and Coptis chinensis Franch. These plants have been used for centuries in traditional medicine for their wide-ranging pharmacological properties. This review emphasizes the latest and comprehensive information on the sources, pharmacology, pharmacokinetics and toxicity of jatrorrhizine. Studies on this alkaloid were collected from scientific internet databases, including the Web of Science, PubMed, ScienceDirect, Google Scholar, Elsevier, Springer, Wiley Online Library and Europe PMC and CNKI, using a combination of keywords involving “jatrorrhizine”, “sources”, “pharmacology,” “pharmacokinetics,” and “toxicology”. Jatrorrhizine exhibits anti-diabetic, antimicrobial, antiprotozoal, anticancer, anti-obesity and hypolipidemic properties, along with central nervous system activities and other beneficial activity. Studies of jatrorrhizine have laid the foundation for its application to the treatment of various diseases, but some issues still exist. Further investigations might emphasize 1) specific curative mechanisms of jatrorrhizine and clinical utility, 2) application prospect in the treatment of metabolic disorders, 3) comprehensive investigations of the toxicity mechanisms and 4) interactions of jatrorrhizine with other pharmaceuticals and development of derivatives.

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“…Several well-characterized UGT substrates were used as "inhibitors" to examine the involvement of UGTs [30] in the glucuronidation of tectorigenin or irigenin. To reduce nonspecific inhibition, the concentration of each inhibitor was determined according to the available literature, namely, 100 µM silibinin for UGT1A1 [31], 50 µM trifluoperazine for UGT1A4 [32], 100 µM 1-naphthol for UGT1A6/1A9 [18,33], and 500 µM fluconazole for UGT2B7 [34].…”

Section: Inhibition Of Glucuronidation Reaction By Chemical Inhibitorsmentioning

confidence: 99%

UGT1A1 and UGT1A9 Are Responsible for Phase II Metabolism of Tectorigenin and Irigenin In Vitro

2022

Molecules

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Tectorigenin and irigenin are biologically active isoflavones of Belamcanda chinensis (L.) DC. Previous studies indicated that both compounds could be metabolized in vivo; however, the kinetic parameters of enzymes involved in the metabolization of tectorigenin and irigenin have not been identified. The aim of this study was to investigate UGTs involved in the glucuronidation of tectorigenin and irigenin and determine enzyme kinetic parameters using pooled human liver microsomes (HLMs) and recombinant UGTs. Glucuronides of tectorigenin and irigenin were identified using high-performance liquid chromatography (HPLC) coupled with mass spectrometry and quantified by HPLC using a response factor method. The results showed that tectorigenin and irigenin were modified by glucuronidation in HLMs. One metabolite of tectorigenin (M) and two metabolites of irigenin (M1 and M2) were detected. Chemical inhibition and recombinant enzyme experiments revealed that several enzymes could catalyze tectorigenin and irigenin glucuronidation. Among them, UGT1A1 and UGT1A9 were the primary enzymes for both tectorigenin and irigenin; however, the former mostly produced irigenin glucuronide M1, while the latter mostly produced irigenin glucuronide M2. These findings suggest that UGT1A1 and UGT1A9 were the primary isoforms metabolizing tectorigenin and irigenin in HLMs, which could be involved in drug–drug interactions and, therefore, should be monitored in clinical practice.

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CYP450 1A2 and multiple UGT1A isoforms are responsible for jatrorrhizine metabolism in human liver microsomes

Cited by 21 publications

References 16 publications

Toxicity and toxicokinetics of the ethanol extract of Zuojin formula

Toxicity and toxicokinetics of the ethanol extract of Zuojin formula

Jatrorrhizine: A Review of Sources, Pharmacology, Pharmacokinetics and Toxicity

UGT1A1 and UGT1A9 Are Responsible for Phase II Metabolism of Tectorigenin and Irigenin In Vitro

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