Berberine and Its Metabolites: Relationship between Physicochemical Properties and Plasma Levels after Administration to Human Subjects

Spinozzi, Silvia; Colliva, Carolina; Camborata, Cecilia; Roberti, Marinella; Ianni, Cristina; Neri, Flavia; Calvarese, Claudio; Lisotti, Andrea; Mazzella, Giuseppe; Roda, Aldo

doi:10.1021/np400607k

Cited by 118 publications

(86 citation statements)

References 27 publications

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“…Plasma samples were collected at intervals of 0, 0.083, 0.167, 0.25, 0.5, 1, 1.5, 2, 3,6,8,12, and 24 h after oral administration and centrifuged at 5000×g for 10 min to separate the plasma. Another six SD rats were housed in metabolic cages with free access to water and food and intragastrically administered with BRB (40 mg/kg) once.…”

Section: Methodsmentioning

confidence: 99%

“…As a major component of RC, BBR has drawn extensive attention recently because of its wide range of effects such as antiinflammatory, lipid-lowering, anti-tumor, and anti-diabetic effects, among others [2][3][4][5] . In vivo studies have revealed that berberrubine (BRB) is the primary metabolite of 9-demethylated BBR that may have potential pharmacological activities [6] . In fact, BRB showed good antibiosis [7] , anti-inflammatory effects [8] , in addition to antioxidant effect on human fibrosarcoma cells [9] and the scavenging effect of reactive oxidative species (ROS) [10] .…”

Section: Introductionmentioning

confidence: 99%

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In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine

et al. 2017

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Berberrubine (BRB) is the primary metabolite of berberine (BBR) that has shown a stronger glucose-lowering effect than BBR in vivo. On the other hand, BRB is quickly and extensively metabolized into berberrubine-9-O-β-D-glucuronide (BRBG) in rats after oral administration. In this study we compared the pharmacokinetic properties of BRB and BRBG in rats, and explored the mechanisms underlying their glucose-lowering activities. C57BL/6 mice with HFD-induced hyperglycemia were administered BRB (50 mg· kg -1 ·d -1 , ig) for 6 weeks, which caused greater reduction in the plasma glucose levels than those caused by BBR (120 mg· kg -1 ·d -1 ) or BRB (25 mg· kg -1 ·d -1 ). In addition, BRB dose-dependently decreased the activity of α-glucosidase in gut of the mice. After oral administration of BRB in rats, the exposures of BRBG in plasma at 3 different dosages (10, 40, 80 mg/kg) and in urine at different time intervals (0-4, 4-10, 10-24 h) were dramatically greater than those of BRB. In order to determine the effectiveness of BRBG in reducing glucose levels, we prepared BRBG from the urine pool of rats, and identified and confirmed it through LC-MS-IT-TOF and NMR spectra. In human normal liver cell line L-O2 in vitro, treatment with BRB or BRBG (5, 20, 50 μmol/L) increased glucose consumption, enhanced glycogenesis, stimulated the uptake of the glucose analog 2-NBDG, and modulated the mRNA levels of glucose-6-phosphatase and hexokinase. However, both BBR and BRB improved 2-NBDG uptake in insulin-resistant L-O2 cells, while BRBG has no effect. In conclusion, BRB exerts a stronger glucose-lowering effect than BBR in HFD-induced hyperglycemia mice. Although BRB significantly stimulated the insulin sensitivity and glycolysis in vitro, BRBG may have a greater contribution to the glucose-lowering effect because it has much greater system exposure than BRB after oral administration of BRB. The results suggest that BRBG is a potential agent for reducing glucose levels.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine

et al. 2017

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“…Chronic administration of BBR at 15 mg/kg body weight/day for three months in humans was shown to result in a plasma concentration of 4 nM of BBR [19]. However, > 20 nM of BBR and its metabolites were found in these subjects.…”

Section: Discussionmentioning

confidence: 92%

Berberine Inhibits Oxygen Consumption Rate Independent of Alteration in Cardiolipin Levels in H9c2 Cells

Chang

Zhang

Chen

et al. 2017

Lipids

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Small clinical studies have shown that oral treatment with the plant alkaloid berberine (BBR) reduces blood glucose levels similar to that of metformin and have promoted its use as a novel anti‐diabetic therapy. However, in vitro studies have shown that high concentrations of BBR potently inhibit cell proliferation through inhibition of mitochondrial function. Cardiolipin (Ptd2Gro) is a key phospholipid required for regulating mitochondrial bioenergetic function. We examined if BBR inhibited oxygen consumption rate in H9c2 cardiac myocytes through alteration in Ptd2Gro metabolism. Treatment of H9c2 cells with BBR resulted in a rapid (within minutes) concentration‐dependent decrease in the oxygen consumption rate (OCR) as determined using a Seahorse XF24 analyzer. Concentrations of BBR as low as 1 µM were effective in inhibiting OCR. In addition, all concentrations of BBR inhibited the fatty acid‐mediated increase in OCR that was observed in untreated cells. Treatment of H9c2 cells with up to 25 µM BBR for 24 h markedly reduced [3H]thymidine incorporation into cells but did not alter the pool size of Ptd2Gro. In contrast, 12.5 µM BBR increased [1‐14C]palmitate incorporation into Ptd2Gro and 12.5 µM and 25 µM BBR reduced [1‐14C]oleate incorporation into Ptd2Gro. Protein kinase C delta (PKCδ) activation through its increased membrane association is known to alter Ptd2Gro distribution within mitochondria. BBR treatment resulted in a decrease in membrane‐associated PKCδ and attenuated the palmitate‐mediated increase in PKCδ membrane‐association. Thus, BBR treatment of H9c2 cardiac myocytes inhibits cellular OCR independent of alteration in Ptd2Gro levels.

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“…It has been reported that BBR inhibited iNOS expression to attenuate NO production. In addition, several reports have shown that BBR induces antioxidant defence by enhancement of the levels of non-enzymatic antioxidants [15,40].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that BBR has abundant pharmacological activities, including antioxidant, anticancer, anti-inflammation, antidepressant, neuroprotection, hepatoprotection, cerebroprotection and cardioprotection [13,14]. In recent years, BBR has been reported to exert beneficial effects in neurodegenerative and neuropsychiatric disorders because of its dual antioxidant and anti-apoptotic activities [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Berberine Protects against Hydrogen Peroxide-Induced Oxidative Damage in PC12 Cells through Activation of ERK1/2 Pathway

Liu¹,

Zeng²,

Gaur³

et al. 2017

Clin Exp Pharmacol

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Oxidative stress is a much-recognized phenomenon linked with the progression of Neurodegenerative Diseases (NDs) due to imbalances in redox homeostasis. Increasing evidence indicates that excessive Reactive Oxygen Species (ROS), impairing the physiological functions of neurons via inducing cell apoptosis, is the main cause of NDs. The drug candidates are required that can effectively protect neurons from oxidative stress insult to slow down the process of neurodegenerative diseases. In present study, we investigated the protective effect and the underlying mechanisms of berberine (BBR, an isoquinoline alkaloid isolated from the herb Rhizoma coptidis, against oxidative damage in PC12 cells. It was found that BBR was able to suppress hydrogen peroxide (H 2 O 2 )-induced cell death in PC12 cells. Flow cytometry revealed that BBR significantly reduced the apoptosis of PC12 cells exposed to H 2 O 2 . Western blot analysis displayed that BBR stimulated the extracellular regulated ERK1/2 survival signaling, while application of PC12 cells with ERK1/2 pathway inhibitor PD98059 blocked the neuroprotective effect of BBR. These results together indicated that BBR is a potential protectant, and it protects PC12 cells against H 2 O 2 toxicity through activated the ERK1/2 pathway.

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Berberine and Its Metabolites: Relationship between Physicochemical Properties and Plasma Levels after Administration to Human Subjects

Cited by 118 publications

References 27 publications

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine

In vitro assessment of the glucose-lowering effects of berberrubine-9-O-β-D-glucuronide, an active metabolite of berberrubine

Berberine Inhibits Oxygen Consumption Rate Independent of Alteration in Cardiolipin Levels in H9c2 Cells

Berberine Protects against Hydrogen Peroxide-Induced Oxidative Damage in PC12 Cells through Activation of ERK1/2 Pathway

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