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    • base compound In summary the metabolism of GEF in HLM and

    2019-10-15

    In summary, the metabolism of GEF in HLM and MLM was extensively studied using a LC–MS-based metabolomic approach. This study identified a total of 34 metabolites and adducts related to GEF (Fig. 10) and identified three new potential reactive metabolites, including two aldehydes and one iminium. Primary amines and GSH–GEF adducts reported previously were also recapitulated in HLM as well. Additionally, we identified that CYP3A4 was the primary enzyme contributing to the formation of the aldehydes, GSH–GEF adduct, and primary amines in liver microsomes. Multiple base compound are involved in the formation of iminium. Further studies are suggested to illustrate the possible role of these potential reactive metabolites in GEF-related adverse effects.
    Acknowledgements We thank Dr. Xiaochao Ma in the School of Pharmacy at the University of Pittsburgh, who kindly provided us the liver of wild type and Cyp3a-null mice.
    Introduction Cytochrome P450 enzymes play major roles in the metabolism of endogenous compounds and biotransformation of xenobiotics [1]. They are found in different locations in the body with higher concentrations in the liver [2]. These enzymes are endogenously synthesized and their syntheses are influenced by both genetic and non-genetic factors. Substances such as drugs, food, herbs and other agents capable of inducing or inhibiting these enzymes could lead to changes in their metabolic capacity. Inhibition of these enzymes is of interest in research and practice because such inhibition is an immediate phenomenon that occurs with the first dose of the inhibitor agent [3]. Enzyme inhibition in pharmacotherapy is a major cause of clinically significant drug interactions [4] and, can either lead to an increase in the bioavailability of a parent drug with extensive first-pass metabolism, or lead to a decreased elimination of compounds with high systemic clearance resulting in substance accumulation and toxicity. Among the identified families of these enzymes involved in metabolism and biotransformation in humans, CYP 3A is the most important. This family is frequently implicated in most drug interactions involving the enzymes because they are highly inducible and can be inhibited by numerous agents including herbs and herbal products [5]. Many enzyme modulators of herbal origin have been found in practice [6], [7], [8], [9], [10]. The prevalence of concurrent use of herbs and herbal preparations with conventional medications is on the increase globally, and some observed cases of herb-drug interactions call for the need to challenge some CYP 450 enzymes with commonly used herbs. Among the plants commonly used in ethnomedicine are Aframomum melegueta (A. melengueta) and Dennettia tripetala (D. tripetala). A. melengueta is claimed to be very effective in the treatment of infectious diseases like tuberculosis, small pox, chicken pox and catarrh including worm infestations and gastrointestinal problems [11], [12]. It has also been shown to possess antidiabetic, antihypertensive, aphrodisiac and testosterone-boosting properties [12], [13]. D. tripetala G. Baker fruit is a common plant used in most communities for cold, fever, typhoid, cough, worm infestation, vomiting, stomach upset and as an appetite enhancer [14]. Scientifically, this plant has shown strong antinociceptic effect comparable to potent opioid agonists and non-steroidal anti-inflammatory drugs [14]. Therefore, in line with the multiplicity of claims and use of most plants including their possible concurrent use with conventional medications, this study evaluated the inhibitory effect of two commonly used herbs, A. melengueta and D. tripetala on CYP 3A enzymes using in vitro and in vivo models.
    Materials and methods
    Results
    Discussion The study assessed the in vitro and in vivo effects of D. tripetala and A. melengueta extracts on CYP450 3A isoenzyme. The result indicated inhibitory activity of the extracts on the enzyme. Some constituents of herbal extracts have been shown to alter CYP450 enzymes causing potential drug interactions [24].