CYP2D plays a major role in berberine metabolism in liver of mice and humans

Berberine is a widely used plant extract for gastrointestinal infections, and is reported to have potential benefits in treatment for diabetes and hypercholesterolemia. It has been suggested that interactions between berberine-containing products and cytochromes P450 (CYPs) exist, but little is known about which CYPs mediate the metabolism of berberine in vivo. In this study, berberine metabolites in urine and feces of mice were analyzed, and the role that CYPs play in producing these metabolites were characterized in liver microsomes from mice (MLM) and humans (HLM), as well as recombinant human CYPs. Eleven berberine metabolites were identified in mice, including 5 unconjugated metabolites, mainly in feces, and 6 glucuronide and sulfate conjugates, predominantly in urine. Three novel berberine metabolites were observed. Three unconjugated metabolites of berberine were produced by MLM, HLM, and recombinant human CYPs. CYP2D6 was the primary recombinant human CYP producing these metabolites, followed by CYP1A2, 3A4, 2E1 and CYP2C19. The metabolism of berberine in MLM and HLM was decreased the most by a CYP2D inhibitor, and moderately by inhibitors of CYP1A and 3A. CYP2D plays a major role in berberine biotransformation, therefore, CYP2D6 pharmacogenetics and potential drug-drug interactions should be considered when berberine is used.

[1]  Wei-Jia Kong,et al.  Bioactivities of berberine metabolites after transformation through CYP450 isoenzymes , 2011, Journal of Translational Medicine.

[2]  Hong-Guang Xie,et al.  Extensive Intestinal First-Pass Elimination and Predominant Hepatic Distribution of Berberine Explain Its Low Plasma Levels in Rats , 2010, Drug Metabolism and Disposition.

[3]  P. R. Vuddanda,et al.  Berberine: a potential phytochemical with multispectrum therapeutic activities , 2010, Expert opinion on investigational drugs.

[4]  T. Cresteil,et al.  Metabolism of sanguinarine in human and in rat: characterization of oxidative metabolites produced by human CYP1A1 and CYP1A2 and rat liver microsomes using liquid chromatography-tandem mass spectrometry. , 2010, Journal of pharmaceutical and biomedical analysis.

[5]  Zhaoyong Hu,et al.  Atrogin-1 Affects Muscle Protein Synthesis and Degradation When Energy Metabolism Is Impaired by the Antidiabetes Drug Berberine , 2010, Diabetes.

[6]  Feng Li,et al.  Metabolism-Mediated Drug Interactions Associated with Ritonavir-Boosted Tipranavir in Mice , 2010, Drug Metabolism and Disposition.

[7]  J. Carrero,et al.  Influence of the CYP2D6 polymorphism and hemodialysis on codeine disposition in patients with end-stage renal disease , 2010, European Journal of Clinical Pharmacology.

[8]  P. Barnes,et al.  Complementary and alternative medicine use among adults and children: United States, 2007. , 2008, National health statistics reports.

[9]  F. Qiu,et al.  Short Communication Isolation and Identification of Urinary Metabolites of Berberine in Rats and Humans , 2008 .

[10]  D. James,et al.  Berberine and Its More Biologically Available Derivative, Dihydroberberine, Inhibit Mitochondrial Respiratory Complex I , 2008, Diabetes.

[11]  L. Ding,et al.  Determination of berberine in human plasma by liquid chromatography-electrospray ionization-mass spectrometry. , 2007, Journal of pharmaceutical and biomedical analysis.

[12]  N. Nakamura,et al.  Pharmacokinetics of Berberine and Its Main Metabolites in Conventional and Pseudo Germ-Free Rats Determined by Liquid Chromatography/Ion Trap Mass Spectrometry , 2006, Drug Metabolism and Disposition.

[13]  D. James,et al.  Berberine, a Natural Plant Product, Activates AMP-Activated Protein Kinase With Beneficial Metabolic Effects in Diabetic and Insulin-Resistant States , 2006, Diabetes.

[14]  T. Tsai,et al.  Hepatobiliary excretion of berberine. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[15]  L. Ereshefsky,et al.  CYP2D6 Inhibition by Selective Serotonin Reuptake Inhibitors: Analysis of Achievable Steady‐State Plasma Concentrations and the Effect of Ultrarapid Metabolism at CYP2D6 , 2002, Pharmacotherapy.

[16]  I. Khan,et al.  High-performance liquid chromatography determination of hydrastine and berberine in dietary supplements containing goldenseal. , 2001, Journal of pharmaceutical sciences.

[17]  K. Bastow,et al.  The 9-position in berberine analogs is an important determinant of DNA topoisomerase II inhibition. , 2000, Anti-cancer drug design.

[18]  R. Weaver,et al.  Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[19]  M. Relling,et al.  Pharmacogenomics: translating functional genomics into rational therapeutics. , 1999, Science.

[20]  Y. Oshima,et al.  Specific CYP3A4 inhibitors in grapefruit juice: furocoumarin dimers as components of drug interaction. , 1997, Pharmacogenetics.

[21]  T. Mizukami,et al.  Inhibitors of DNA topoisomerase I and II isolated from the Coptis rhizomes. , 1995, Planta medica.

[22]  H. Yamazaki,et al.  Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. , 1994, The Journal of pharmacology and experimental therapeutics.

[23]  W. Trager,et al.  Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline. , 1993, Chemical research in toxicology.

[24]  P. Watkins,et al.  Identification of glucocorticoid-inducible cytochromes P-450 in the intestinal mucosa of rats and man. , 1987, The Journal of clinical investigation.

[25]  T. Ikekawa,et al.  Antitumor activity of berberrubine derivatives. , 1976, Gan.

[26]  T. Subbaiah,et al.  Berberine sulfate: antimicrobial activity, bioassay, and mode of action. , 1969, Canadian journal of microbiology.

[27]  Neil B. Sandson.  Drug-drug interactions: the silent epidemic. , 2005, Psychiatric services.

[28]  Da-yuan Zhu,et al.  Identification of three sulfate-conjugated metabolites of berberine chloride in healthy volunteers' urine after oral administration. , 2002, Acta pharmacologica Sinica.

[29]  K. Thummel,et al.  In vitro and in vivo drug interactions involving human CYP3A. , 1998, Annual review of pharmacology and toxicology.

[30]  N. K. Dutta,et al.  Berberine and chloramphenicol in the treatment of cholera and severe diarrhoea. , 1967, Journal of the Indian Medical Association.