Differential inhibition of CYP1-catalyzed regioselective hydroxylation of estradiol by berberine and its oxidative metabolites
| Autor: | Yu Ping Chang, Yune-Fang Ueng, Keng-Chang Tsai, Chiung-Chiao Huang, Chien-Chang Shen |
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| Rok vydání: | 2015 |
| Předmět: |
Berberine
Metabolite Pharmaceutical Science Pharmacology Hydroxylation chemistry.chemical_compound Non-competitive inhibition Cytochrome P-450 CYP1A2 Cytochrome P-450 CYP1A1 Cytochrome P-450 Enzyme Inhibitors Humans Computer Simulation Pharmacology (medical) Estradiol biology Alkaloid CYP1A2 Cytochrome P450 Coptis chinensis biology.organism_classification Recombinant Proteins Isoenzymes Molecular Docking Simulation body regions Biochemistry chemistry Cytochrome P-450 CYP1B1 biology.protein Oxidation-Reduction |
| Zdroj: | Drug Metabolism and Pharmacokinetics. 30:374-383 |
| ISSN: | 1347-4367 |
| DOI: | 10.1016/j.dmpk.2015.08.006 |
| Popis: | Berberine is a pharmacologically active alkaloid present in widely used medicinal plants, such as Coptis chinensis (Huang-Lian). The hormone estradiol is oxidized by cytochrome P450 (CYP) 1B1 to primarily form the genotoxic metabolite 4-hydroxyestradiol, whereas CYP1A1 and CYP1A2 predominantly generate 2-hydroxyestradiol. To illustrate the effect of berberine on the regioselective oxidation of estradiol, effects of berberine and its metabolites on CYP1 activities were studied. Among CYP1s, CYP1B1.1, 1.3 (L432V), and 1.4 (N453S)-catalyzed 4-hydroxylation were preferentially inhibited by berberine. Differing from the competitive inhibition of CYP1B1.1 and 1.3, N453S substitution in CYP1B1 allowed a non-competitive or mixed-type pattern. An N228T in CYP1B1 highly decreased its activity and preference to 4-hydroxylation. A reverse mutation of T223N in CYP1A2 retained its 2-hydroxylation preference, but enhanced its inhibition susceptibility to berberine. Compared with berberine, metabolites demethyleneberberine and thalifendine caused weaker inhibition of CYP1A1 and CYP1B1 activities. Unexpectedly, thalifendine was more potent than berberine in the inhibition of CYP1A2, in which case an enhanced interaction through polar hydrogen-π bond was predicted from the docking analysis. These results demonstrate that berberine preferentially inhibits the estradiol 4-hydroxylation activity of CYP1B1 variants, suggesting that 4-hydroxyestradiol-mediated toxicity might be reduced by berberine, especially in tissues/tumors highly expressing CYP1B1. |
| Databáze: | OpenAIRE |
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