scholarly journals Endocannabinoid turnover in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Stephen P.H. Alexander ◽  
Patrick Doherty ◽  
Christopher J. Fowler ◽  
Jürg Gertsch ◽  
Mario Van der Stelt
Keyword(s):  
Cytochrome P450 ◽  
Phospholipase D ◽  
Cytochrome P450 Enzyme ◽  
Facilitated Diffusion ◽  
In Vitro Experiments ◽  
Diacylglycerol Lipase ◽  
P450 Enzyme ◽  
Key Enzyme

The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [28]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [17]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [70]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [62]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [5, 23, 72].

scholarly journals Endocannabinoid turnover (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Stephen P.H. Alexander ◽  
Patrick Doherty ◽  
Christopher J. Fowler ◽  
Jürg Gertsch ◽  
Mario Van der Stelt
Keyword(s):  
Cytochrome P450 ◽  
Phospholipase D ◽  
Cytochrome P450 Enzyme ◽  
Facilitated Diffusion ◽  
In Vitro Experiments ◽  
Diacylglycerol Lipase ◽  
P450 Enzyme ◽  
Key Enzyme

The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [19]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [12]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [49]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has recently been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [43]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [4, 16, 51].

scholarly journals Unraveling the Metabolic Routes of Retapamulin: Insights into Drug Development of Pleuromutilins

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Feifei Sun ◽  
Huiyan Zhang ◽  
Gerard Bryan Gonzales ◽  
Jinhui Zhou ◽  
Yi Li ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Metabolic Pathways ◽  
Enzyme Inhibitors ◽  
Side Chain ◽  
Cytochrome P450 Enzyme ◽  
Cytochrome P450 Enzymes ◽  
Short Term ◽  
P450 Enzyme

ABSTRACT Retapamulin, a semisynthetic pleuromutilin derivative, is exclusively used for the topical short-term medication of impetigo and staphylococcal infections. In the present study, we report that retapamulin is adequately and rapidly metabolized in vitro via various metabolic pathways, such as hydroxylation, including mono-, di-, and trihydroxylation, and demethylation. Like tiamulin and valnemulin, the major metabolic routes of retapamulin were hydroxylation at the 2β and 8α positions of the mutilin moiety. Moreover, in vivo metabolism concurred with the results of the in vitro assays. Additionally, we observed significant interspecies differences in the metabolism of retapamulin. Until now, modifying the side chain was the mainstream method for new drug discovery of the pleuromutilins. This approach, however, could not resolve the low bioavailability and short efficacy of the drugs. Considering the rapid metabolism of the pleuromutilins mediated by cytochrome P450 enzymes, we propose that blocking the active metabolic site (C-2 and C-8 motif) or administering the drug in combination with cytochrome P450 enzyme inhibitors is a promising pathway in the development of novel pleuromutilin drugs with slow metabolism and long efficacy.

scholarly journals The role of cytochrome P450 enzymes in carcinogen activation and detoxication: an in vivo–in vitro paradox

2018 ◽  
Vol 39 (7) ◽  
pp. 851-859 ◽  
Author(s):  
Lindsay Reed ◽  
Volker M Arlt ◽  
David H Phillips
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 Enzyme ◽  
Cytochrome P450 Enzymes ◽  
Predominant Role ◽  
Enzyme Systems ◽  
P450 Enzyme

Cytochrome P450 enzyme systems have been widely used in vitro to determine the pathways of activation of procarcinogens, but paradoxically, these same enzymes can play a more predominant role in carcinogen detoxification in vivo.

scholarly journals Chlorogenic Acid as a Model Compound for Optimization of an In Vitro Gut Microbiome-Metabolism Model

Proceedings ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 31 ◽  
Author(s):  
Olivier Mortelé ◽  
Elias Iturrospe ◽  
Annelies Breynaert ◽  
Christine Lammens ◽  
Xavier Basil Britto ◽  
...  
Keyword(s):  
Chlorogenic Acid ◽  
Gut Microbiome ◽  
Model Compound ◽  
In Vitro Models ◽  
Cytochrome P450 Enzyme ◽  
Flight Mass Spectrometry ◽  
P450 Enzyme ◽  
Analytical Phase

It has been believed that the metabolism of xenobiotics occurred mainly by the cytochrome P450 enzyme system in the liver. However, recent data clearly suggest a significant role for the gut microbiota in the metabolism of xenobiotic compounds. This microbiotic biotransformation could lead to differences on activation, inactivation and possible toxicity of these compounds. In vitro models are generally used to study the colonic biotransformation as they allow easy dynamic and multiple sampling over time. However, to ensure this accurately mimics communities in vivo, the pre-analytical phase requires optimization. Chlorogenic acid, a polyphenolic compound abundantly present in the human diet, was used as a model compound to optimize a ready-to-use gut microbiome biotransformation platform. Samples of the in vitro gastrointestinal dialysis-model with colon stage were analyzed by liquid chromatography coupled to high resolution time-of-flight mass spectrometry. Complementary screening approaches were also employed to identify the biotransformation products.

2020 FDA Drug-drug Interaction Guidance: A Comparison Analysis and Action Plan by Pharmaceutical Industrial Scientists

2020 ◽  
Vol 21 (6) ◽  
pp. 403-426 ◽  
Author(s):  
Sirimas Sudsakorn ◽  
Praveen Bahadduri ◽  
Jennifer Fretland ◽  
Chuang Lu
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Drug Interactions ◽  
Action Plan ◽  
European Medicines Agency ◽  
Cytochrome P450 Enzyme ◽  
Interaction Studies ◽  
P450 Enzyme ◽  
Us Fda

Background: In January 2020, the US FDA published two final guidelines, one entitled “In vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry” and the other entitled “Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry”. These were updated from the 2017 draft in vitro and clinical DDI guidance. Methods: This study is aimed to provide an analysis of the updates along with a comparison of the DDI guidelines published by the European Medicines Agency (EMA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) along with the current literature. Results: The updates were provided in the final FDA DDI guidelines and explained the rationale of those changes based on the understanding from research and literature. Furthermore, a comparison among the FDA, EMA, and PMDA DDI guidelines are presented in Tables 1, 2 and 3. Conclusion: The new 2020 clinical DDI guidance from the FDA now has even higher harmonization with the guidance (or guidelines) from the EMA and PMDA. A comparison of DDI guidance from the FDA 2017, 2020, EMA, and PMDA on CYP and transporter based DDI, mathematical models, PBPK, and clinical evaluation of DDI is presented in this review.

scholarly journals Biotransformation of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX) by a Rabbit Liver Cytochrome P450: Insight into the Mechanism of RDX Biodegradation by Rhodococcus sp. Strain DN22

2003 ◽  
Vol 69 (3) ◽  
pp. 1347-1351 ◽  
Author(s):  
Bharat Bhushan ◽  
Sandra Trott ◽  
Jim C. Spain ◽  
Annamaria Halasz ◽  
Louise Paquet ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Product Distribution ◽  
Rabbit Liver ◽  
Ring Cleavage ◽  
Cytochrome P450 Enzyme ◽  
Intact Cells ◽  
Cytochrome P450 2B4 ◽  
Elemental Analyses ◽  
P450 Enzyme ◽  
Key Enzyme

ABSTRACT A unique metabolite with a molecular mass of 119 Da (C2H5N3O3) accumulated during biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) by Rhodococcus sp. strain DN22 (D. Fournier, A. Halasz, J. C. Spain, P. Fiurasek, and J. Hawari, Appl. Environ. Microbiol. 68:166-172, 2002). The structure of the molecule and the reactions that led to its synthesis were not known. In the present study, we produced and purified the unknown metabolite by biotransformation of RDX with Rhodococcus sp. strain DN22 and identified the molecule as 4-nitro-2,4-diazabutanal using nuclear magnetic resonance and elemental analyses. Furthermore, we tested the hypothesis that a cytochrome P450 enzyme was responsible for RDX biotransformation by strain DN22. A cytochrome P450 2B4 from rabbit liver catalyzed a very similar biotransformation of RDX to 4-nitro-2,4-diazabutanal. Both the cytochrome P450 2B4 and intact cells of Rhodococcus sp. strain DN22 catalyzed the release of two nitrite ions from each reacted RDX molecule. A comparative study of cytochrome P450 2B4 and Rhodococcus sp. strain DN22 revealed substantial similarities in the product distribution and inhibition by cytochrome P450 inhibitors. The experimental evidence led us to propose that cytochrome P450 2B4 can catalyze two single electron transfers to RDX, thereby causing double denitration, which leads to spontaneous hydrolytic ring cleavage and decomposition to produce 4-nitro-2,4-diazabutanal. Our results provide strong evidence that a cytochrome P450 enzyme is the key enzyme responsible for RDX biotransformation by Rhodococcus sp. strain DN22.

Sign in / Sign up

Export Citation Format

Share Document