Effects Of Components In The Commonly Used Traditional Chinese Medicines On The Activity Of Cytochrome P450 1A2

Herbal medicines are often used as auxiliary treatment, in combination with westernmedicines. Herbal medicines probably influence the activity of drug metabolizing enzymes,increasing or reducing the effectiveness of treatment or the toxicity of co-administrationsand thereby affect human health, leading to the occurrence of herb-drug interactions.Meanwhile different enzyme concentrations, substrate concentrations and incubation timeshave a great impact on the results. The data reported by different labs is not comparable toothers. This requires a systematic study to explore the traditional medicines on theactivities of drug metabolizing enzymes.Human cytochrome P450 1A2 (CYP1A2) is the single most importantdrug-metabolizing enzyme. It accounts for roughly 13% of the total cytochrome P450 inhuman liver microsomes and metabolizes more than 5% of the clinically used drugs.CYP1A2 is the target for a number of herb-drug interactions of significant clinical concern,well-known examples are the inhibition of CYP1A2 by Echinacea rendering the rate ofcaffeine elimination less efficient, and the inhibition of the same CYP enzyme by St.John's wort. The knowledge of herb-drug interactions associated to this enzyme is ofinterestingly importance during multidrug treatments.In present study, in vitro experiments using recombinant CYP1A2 were carried out topredict potential herb-drug interaction involving the enzyme prior to studies in vivo. Twohundred and twenty-six active components extracted from commonly used traditionalChinese medicines (TCM) were investigated, and 13 of them showed modest to potentinhibition with IC50 values ranged from 0.096 to 5.31μM. To further examined theirimpacts on the metabolism of CYP1A2, two (chrysin and nuciferine) among the 13compounds were orally dosed to rats along with phenacetin as a probe. Nuciferineexhibited alteration of the pharmacokinetic parameters of phenacetin, which implied thatadditional attention should be paid when nuciferine is administered concomitantly withmany clinical drugs. However, chrysin didn't exhibit alteration of the pharmacokineticparameters of phenacetin. Due to the number of herbal medicines is large and thetraditional screening technology by testing each herbal medicine to enzyme in vitro or invivo was not only costly, but also inefficiency. It was not meet the rapid screening oftraditional Chinese medicine database. In present study, we started our analysis byconstructing the pharmaphore model of CYP1A2. The 3D structures of CYP1A2 and its homologues and some inhibitors of CYP1A2 reported were used as the training templates.Then up to 226 herb ingredients tested in vitro by our group before were used to validateand derive the pharmaphore model of CYP1A2. Based on the 3D structures of CYP1A2,an active site and stable parameters for docking were chosen as a tandem process forscreening. Eighteen compounds were selected from one thousands compounds. Finally,eighteen compounds were tested in vitro and five compounds have shown inhibition onCYP1A2. The model was validated by the experiment in vitro where accuracy was 27.8%.