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125-73-5Relevant articles and documents
Inhibitory effects of polyphenols and their colonic metabolites on CYP2D6 enzyme using two different substrates
Csepregi, Rita,Fliszár-Nyúl, Eszter,Mladěnka, P?emysl,Mohos, Violetta,Poór, Miklós
, (2020)
Polyphenolic compounds (including flavonoids, chalcones, phenolic acids, and furanocoumarins) represent a common part of our diet, but are also the active ingredients of several dietary supplements and/or medications. These compounds undergo extensive metabolism by human biotransformation enzymes and the microbial flora of the colon. CYP2D6 enzyme metabolizes approximately 25% of the drugs, some of which has narrow therapeutic window. Therefore, its inhibition can lead to the development of pharmacokinetic interactions and the disruption of drug therapy. In this study, the inhibitory effects of 17 plant-derived compounds and 19 colonic flavonoid metabolites on CYP2D6 were examined, employing two assays with different test substrates. The O-demethylation of dextromethorphan was tested employing CypExpress 2D6 kit coupled to HPLC analysis; while the O-demethylation of another CYP2D6 specific substrate (AMMC) was investigated in a plate reader assay with BioVision Fluorometric CYP2D6 kit. Interestingly, some compounds (e.g., bergamottin) inhibited both dextromethorphan and AMMC demethylation; however, certain substances proved to be inhibitors only in one of the assays applied. Our results demonstrate that some polyphenols and colonic metabolites are inhibitors of CYP2D6-catalyzed reactions. Nevertheless, the inhibitory effects showed strong substrate dependence.
Dynamic modeling of cytochrome P450 inhibition in vitro: Impact of inhibitor depletion on IC50 shift
Berry, Loren M.,Zhao, Zhiyang,Lin, Min-Hwa Jasmine
, p. 1433 - 1441 (2013)
The impact of inhibitor depletion on the determination of shifted IC 50 (IC50 determined after 30 minutes of preincubation with inhibitor) is examined. In addition, IC50-shift data are analyzed using a mechanistic model that incorporates the processes of inhibitor depletion, as well as reversible and time-dependent inhibition. Anomalies such as a smaller-than-expected shift in IC50 and even increases in IC50 with preincubation were explained by the depletion of inhibitor during the preincubation. The IC50-shift assay remains a viable approach to characterizing a wide range of reversible and time-dependent inhibitors. However, as with more traditional time-dependent inactivation methods, it is recommended that IC50-shift experimental data be interpreted with some knowledge of the magnitude of inhibitor depletion. For the most realistic classification of time-dependent inhibitors using IC 50-shift methods, shifted IC50 should be calculated using observed inhibitor concentrations at the end of the incubation rather than nominal inhibitor concentrations. Finally, a mechanistic model that includes key processes, such as competitive inhibition, enzyme inactivation, and inhibitor depletion, can be used to describe accurately the observed IC50 and shifted IC50 curves. For compounds showing an IC50 fold shift >1.5 based on the observed inhibitor concentrations, reanalyzing the IC50-shift data using the mechanistic model appeared to allow for reasonable estimation of Ki, KI, and kinact directly from the IC50 shift experiments.
Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products
Appiah-Opong, Regina,Commandeur, Jan N.M.,van Vugt-Lussenburg, Barbara,Vermeulen, Nico P.E.
, p. 83 - 91 (2007)
Curcumin (diferuloylmethane) is a major yellow pigment and dietary component derived from Curcuma longa. It has potent anti-inflammatory, anticarcinogenic, antioxidant and chemoprotective activities among others. We studied the interactions of curcumin, a mixture of its decomposition products, and four of its individually identified decomposition products (vanillin, vanillic acid, ferulic aldehyde and ferulic acid) on five major human drug-metabolizing cytochrome P450s (CYPs). Curcumin inhibited CYP1A2 (IC50, 40.0 μM), CYP3A4 (IC50, 16.3 μM), CYP2D6 (IC50, 50.3 μM), CYP2C9 (IC50, 4.3 μM) and CYP2B6 (IC50, 24.5 μM). Curcumin showed a competitive type of inhibition towards CYP1A2, CYP3A4 and CYP2B6, whereas a non-competitive type of inhibition was observed with respect to CYP2D6 and CYP2C9. The inhibitory activity towards CYP3A4, shown by curcumin may have implications for drug-drug interactions in the intestines, in case of high exposure of the intestines to curcumin upon oral administration. In spite of the significant inhibitory activities shown towards the major CYPs in vitro, it remains to be established, whether curcumin will cause significant drug-drug interactions in the liver, given the reported low systemic exposure of the liver to curcumin. The decomposition products of curcumin showed no significant inhibitory activities towards the CYPs investigated, and therefore, are not likely to cause drug-drug interactions at the level of CYPs.
Benchmarking of laboratory evolved unspecific peroxygenases for the synthesis of human drug metabolites
Gomez de Santos, Patricia,Cervantes, Fadia V.,Tieves, Florian,Plou, Francisco J.,Hollmann, Frank,Alcalde, Miguel
, p. 1827 - 1831 (2019)
By mimicking the role of human liver P450 monooxygenases, fungal unspecific peroxygenases (UPOs) can perform a range of highly selective oxyfunctionalization reactions on pharmacological compounds, including O-dealkylations and hydroxylations, thereby simulating drug metabolism. Here we have benchmarked human drug metabolite (HDM) synthesis by several evolved UPO mutants, focusing on dextromethorphan, naproxen and tolbutamide. The HDM from dextromethorphan was prepared at the semi-preparative scale as a proof of production. The structural analysis of mutations involved in the synthesis of HDMs highlights the heme access channel as the main feature on which to focus when designing evolved UPOs. These variants are becoming emergent tools for the cost-effective synthesis of HDMs from next-generation drugs.
Potent inhibition of yeast-expressed CYP2D6 by dihydroquinidine, quinidine, and its metabolites
Ching, Michael S.,Blake, Carolyn L.,Ghabrial, Hany,Ellis, S. Wynne,Lennard, Martin S.,Tucker, Geoffrey T.,Smallwood, Richard A.
, p. 833 - 837 (1995)
The inhibitory effects of dihydroquinidine, quinidine and several quinidine metabolites on cytochrome P450 2D6 (CYP2D6) activity were examined. CYP2D6 heterologously expressed in yeast cells O-demethylated dextromethorphan with a mean K(m) of 5.4 μM and a V(max) of 0.47 nmol/min/nmol. Quinidine and dihydroquinidine both potently inhibited CYP2D6 metabolic activity (mean K(i) = 0.027 and 0.013 μM, respectively) in yeast microsomes and in human liver microsomes. The metabolites, 3-hydroxyquinidine, O-desmethylquinidine and quinidine N-oxide also inhibited CYP2D6, but their K(i) values (0.43 to 2.3 μM) were one to two orders of magnitude weaker than the values for quinidine and dihydroquinidine. There was a trend towards an inverse relationship between K(i) and lipophilicity (r = -0.90, N = 5, P = 0.07), as determined by the retention-time parameter k' using reverse-phase HPLC. Thus, although the metabolites of quinidine have the capacity to inhibit CYP2D6 activity, quinidine and the impurity dihydroquinidine are the important inhibitors of CYP2D6.
Characterization of mixtures of recombinant human cytochrome P450s as a screening model for metabolic stability in drug discovery
Hagen,Olsen,Andersen,Tjrnelund,Hansen
, p. 749 - 759 (2002)
1. Recombinant human cytochrome P450 (rhCYP) has become an important screening model in drug metabolism studies due to the high cost of human and animal hepatic tissue. Until now, rhCYPs have been evaluated and used as separate forms, but a mixture of CYP forms comparable with the human liver could be of value in early drug discovery. 2. In the present study, rhCYP2C9, rhCYP2D6 and rhCYP3A4 co-expressed with reductase in Escerichia coli were mixed and evaluated with regards to kinetic properties (Km and Vmax). Furthermore, antioxidant was added to investigate whether a free radical scavenger would affect the kinetic parameters. Results were compared with data obtained in human liver microsomes (HLM). 3. Results showed a good correlation between mixed rhCYP data and HLM data for Km and Vmax. Km varied m for CYP2D6 varied up to 4.5-fold. Vmax differed up to 3-fold between matrices for the CYP forms investigated. However, the discrepancy in Vmax may depend on the anticipated level of each form in HLM. The addition of antioxidant increased Vmax for CYP2C9 and CYP2D6 by 75 and 50%, respectively, whereas Vmax for CYP3A4 was unchanged. 4. In conclusion, the rhCYP mixture shows promising results as a predictor of CYP kinetic parameters. Furthermore, addition of antioxidant can in certain cases increase catalytic activity.
Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6
Yamaori, Satoshi,Okamoto, Yasuka,Yamamoto, Ikuo,Watanabe, Kazuhito
, p. 2049 - 2056 (2011)
Δ9-Tetrahydrocannabinol, cannabidiol (CBD), and cannabinol are the three major cannabinoids contained in marijuana, which are devoid of nitrogen atoms in their structures. In this study, we investigated the inhibitory effects of the major phytocannabinoids on the catalytic activity of human CYP2D6. These major cannabinoids inhibited the 3-[2-(N,N-diethyl-N- methylammonium)ethyl]-7-methoxy-4-methylcoumarin (AMMC) and dextromethorphan O-demethylase activities of recombinant CYP2D6 and pooled human liver microsomes in a concentration-dependent manner (IC50 =4.01-24.9 μM), indicating the strongest inhibitory potency of CBD. However, these cannabinoids showed no or weak metabolism-dependent inhibition. CBD competitively inhibited the CYP2D6 activities with the apparent Ki values of 1.16 to 2.69 μM. To clarify the structural requirement for CBD-mediated CYP2D6 inhibition, effects of CBD-related compounds on the AMMC O-demethylase activity of recombinant CYP2D6 were examined. Olivetol (IC50 =7.21 μM) inhibited CYP2D6 activity as potently as CBD did (IC50 =6.52 μM), whereas d-limonene did not show any inhibitory effect. Pentylbenzene failed to inhibit CYP2D6 activity. Furthermore, neither monomethyl nor dimethyl ethers of CBD inhibited the activity. Cannabidivarin having a propyl side chain inhibited CYP2D6 activity; its inhibitory effect (IC50 = 10.2 μM) was less potent than that of CBD. On the other hand, orcinol and resorcinol showed lack of inhibition. The inhibitory effect of CBD on CYP2D6 activity was more potent than those of 16 compounds without nitrogen atoms tested, such as progesterone. These results indicated that CBD caused potent direct CYP2D6 inhibition, in which two phenolic hydroxyl groups and the pentyl side chain of CBD may play important roles. Copyright
Synthesis of potent sigma-1 receptor ligands via fragmentation of dextromethorphan
Arrington, Mark P.,Brown, Claire,Schwartz, C. Eric
, p. 1807 - 1809 (2004)
Treatment of dextromethorphan 1 with various alkylating agents followed by base treatment led to Hoffman-type elimination reactions to produce a series of tricyclic derivatives, 6. These derivatives were characterized in vitro as sigma-1 receptor ligands.
Anticonvulsant effects of new morphinan derivatives
Kim, Hyoung-Chun,Nabeshima, Toshitaka,Jhoo, Wang-Kee,Ko, Kwang Ho,Kim, Won-Ki,Shin, Eun-Joo,Cho, Minkyoung,Lee, Phil Ho
, p. 1651 - 1654 (2001)
We synthesized a series of compounds that are modified in positions 3 and 17 of the morphinan ring system, with the intention of developing ideal anticonvulsant agents. We examined the effects of these compounds on kainic acid (KA)-induced seizures, and on locomotor patterns in rats. We found that compounds 5, 6, and 8 exhibit novel anticonvulsant effects, with negligible psychotropic effects.
Selective Oxyfunctionalisation Reactions Driven by Sulfite Oxidase-Catalysed In Situ Generation of H2O2
van Schie, Morten M. C. H.,Kaczmarek, Alexander T.,Tieves, Florian,Gomez de Santos, Patricia,Paul, Caroline E.,Arends, Isabel W. C. E.,Alcalde, Miguel,Schwarz, Günter,Hollmann, Frank
, p. 3186 - 3189 (2020)
H2O2 can be accepted by several peroxygenases as a clean oxidant, able to supply both the necessary electrons and oxygen atom at the same time. The biocatalysts, in turn, are able to catalyse an array of interesting oxygen insertion reactions at enantio- and regio-selectivities hard to attain with classical chemical methods. The sensitivity of most peroxygenases towards H2O2, however, requires this oxidant to be generated in situ. Here, we suggest the application of (modified) sulfite oxidases to couple the oxidation of sulfites to the reduction of oxygen. This enables us to use calcium sulfite, an industrial waste product from scrubbing flue gases, as an electron donor to reduce oxygen. This will supply the required peroxide in a controlled manner and enables us to perform these challenging reactions at the expense of simple salts.