Shijie Cao

Berberine, a bioactive alkaloid isolated from several herbal substances, possesses multiple pharmacological effects, including antimicrobial, antidiabetic, anticancer activities. Meanwhile, berberine undergoes extensive metabolism after oral administration which results in its extremely low plasma exposure. Therefore, it is believed that the metabolites of berberine also contribute a lot to its pharmacological effects. Along these lines, this review covers the metabolism studies of berberine in terms of its metabolic pathways and metabolic organs based on the identified metabolites, and it also covers the pharmacological activities of its active metabolites. In brief, the predominant metabolic pathways of berberine are demethylation, demethylenation, reduction, hydroxylation and subsequent conjugation in vivo. Active metabolites such as columbamine, berberrubine and demethyleneberberine also exhibit similar pharmacological effects by comparison with berberine, such as antioxidant, anti-inflammatory, antitumor, antimicrobial, hepatoprotective, neuroprotective, hypolipidemic and hypoglycemic effects. Overall, berberine together with its metabolites formed the material basis of berberine in vivo.

Berberine, an isoquinoline alkaloid from Coptidis Rhizoma, has been characterized as a potential anticancer drug due to its good anti-tumor effects. However, the molecular mechanisms involved in anti-gastric cancer remain poorly understood. Herein, the role of berberine in gastric cancer suppression by inducing cytostatic autophagy in vitro and in vivo was first investigated. Results showed that berberine induced an obvious growth inhibitory effect on gastric cancer BGC-823 cells without toxicity to human peripheral blood mononuclear cells. Treatment with berberine triggered cell autophagy, as demonstrated by the punctuate distribution of monodansylcadaverine staining and GFP-LC3, as well as the LC3-II, Beclin-1 and p-ULK1 promotion, and p62 degradation. Inhibition of autophagy by 3-MA, CQ, Baf-A1 and BECN1 siRNA obviously increased cell viability of berberine-exposed gastric cancer cells, which confirmed the anti-cancer role of autophagy induced by berberine. Mechanistic studies showed that berberine inhibited mTOR, Akt and MAPK (ERK, JNK and p38) pathways thereby inducing autophagy. Inhibition of above pathways increases berberine induced autophagy and cytotoxicity. Interestingly, mTOR/p70S6K was inhibited by the MAPK but not Akt. Furthermore, inhibition of autophagy reversed berberine down-regulated mTOR, Akt and MAPK. In xenografts, the berberine induced autophagy leads to suppression of tumor proliferation with no side-effect, and western blotting displayed an apparent attenuation of p-mTOR, p-p70S6K, p-Akt, p-ERK, p-JNK and p-p38 in tumors from berberine treated mice. Briefly, these results indicated that berberine repressed human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt, and provided a molecular basis for the treatment of gastric cancer.

Berberine, a well-known alkaloid, has been proved to possess various pharmacological activities. Previous studies demonstrated that berberine could be extensively metabolized and the metabolites also contributed to its therapeutic effects. However, as for berberine’s metabolites, especially phase II metabolites, pharmacokinetics and excretion studies were rarely reported. The objective of this study was to thoroughly investigate the pharmacokinetic and excretion profiles of berberine and its nine metabolites, namely, berberrubine (M1), demethyleneberberine (M2), jatrorrhizine (M3), jatrorrhizine-3- O-β -D-glucuronide (M4), jatrorrhizine-3- O -sulfate (M5), thalfendine-10- O-β -D-glucuronide (M6), berberrubine-9- O-β -D-glucuronide (M7), demethyleneberberine-2- O -sulfate (M8) and demethyleneberberine-2- O-β -D-glucuronide (M9) in rats. An accurate and reliable LC-MS/MS method was developed and validated for the determination of berberine and its nine metabolites in rat biosamples. Pharmacokinetic profiles of berberine and its nine metabolites were obtained after a single intravenous administration (4.0 mg/kg) and oral administration (48.2, 120 or 240 mg/kg) of berberine in rats. For excretion study, rats were intragastrically administered a single dose of 48.2 mg/kg berberine. Our results showed that berberine could be metabolized rapidly and all the nine metabolites could be detected in vivo . The absolute bioavailability of berberine was 0.37 ± 0.11%. As for the AUC 0–48 h values, phase II metabolites were much higher than those of phase I metabolites, suggesting that phase II metabolites were the major metabolites exist in blood circulation. 18.6% of the berberine was excreted in feces as berberrubine (M1). The total recovery of berberine and its nine metabolites from urine, bile and feces was 41.2%. This is the first systematic study about the pharmacokinetics and excretion of berberine and its nine metabolites, which will be beneficial for both better understanding the clinical effects and further development of berberine.