Interaction Studies, Based On Drug Metabolizing Enzymes In Chinese Medicine

Cytochrome P450 (CYP) enzymes are a family of heme-containing proteins and rank first among the phase I biotransformation enzymes in terms of drug metabiolism and drug-drug interactions. Drug interactions can frequently arise when drugs are coadministered and one drug modulates the metabolic clearance of the second drug through inhibition or induction of a specific CYP enzyme, possibly leading to adverse drug interactions(ADR), including some fatal interactions. Recently, drug-drug interactions based on CYP and the modulated mechanism of CYP by drugs are more concerned. The safety and ADR of Traditional Chinese medicine (TCM) frequently arise with an increasing consumption of TCM, where they are often administrated in combination and the constitutes in herbal preparations maybe substrates, inhibitors or inducers of CYP, so it maybe exist herb-herb interactions based on CYP. CYP, the molecular basis of drug-drug interaction in modern pharmacology was taken into the study of herb-herb interaction. We systemically studied the relationship between eighteen incompatible medicaments and CYP, and the goal of this study was to provide experimental evidences to the mode of herb-herb interaction based on CYP and the mechanism of incomepatible medicaments.Salvia miltiorrhiza, Sophora flaveacens and Panax gingseng coadministered with Veratrum nigrum resulted in decreasing P450 content and inhibition of the enzyme activity of CYP3A and CYP2E1, which suggested the inhibitory effect on CYP3A and CYP2E1 may have impact on the metabolism of toxic constitutes in Veratrum nigrum and cause the toxicity increasing. Trichosanthes kirilowii, Bletilla striata, Pinellia ternata, and Fritillaria cirrhosa coadministered with Aconitum carmichaeli had an obvious inhibitory effect on the CYP3A and CYP1A2 at the mRNA, protein and catalytic activity level. Using LC/MS and in vitro metabolism assay, we found and characterized six metabolites of aconitine in rat liver microsomal incubations. Structure-activity relationship analysis showed that the toxicity of metabolites were lower than aconitine. Using HPLC and chemical inhibition method , We showed that CYP 3A and CYP1A2 were the major enzymes responsible for the metabolism of...