Biotransformation of Benfluron by Rat Hepatic Cytochrome P450. Identification of Individual CYP-Enzymes Involved in Biotransformation of Benfluron, Prospective Antineoplastic Based on Benzo[c]fluorene

Benfluron, 5-[2-(dimethylamino)ethoxy]-7H-benzo[c]fluoren-7-one hydrochloride, a prospective antineoplastic agent, is metabolised by cytochromes P450 to N-demethyl and 9-hydroxy derivatives. To prove the participation of individual cytochrome P450 isoforms in formation of these metabolites, selective induction of cytochromes P450, inhibition of benfluron biotransformation using inhibitors specific for individual cytochromes P450, and inhibition by benfluron of "marker" enzyme activities characteristic of certain cytochromes P450 were used. N-Demethylbenfluron appears to be formed mainly by the cytochromes P450 of the 3A, 2B and 2C subfamilies with possible participation of the isoform 2E1; 9-hydroxybenfluron is formed with participation of cytochromes P450 belonging to 1A, and most probably to 3A and 2E1 enzymes. The fact that benfluron is in this respect a relatively promiscuous substrate may be an advantage because its metabolism should not be influenced by the absence or low activity of some cytochrome P450 isoforms and by possible drug interactions.

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In Silico Prediction of Drug–Drug Interactions Mediated by Cytochrome P450 Isoforms

Pharmaceutics ◽

10.3390/pharmaceutics13040538 ◽

2021 ◽

Vol 13 (4) ◽

pp. 538

Author(s):

Alexander V. Dmitriev ◽

Anastassia V. Rudik ◽

Dmitry A. Karasev ◽

Pavel V. Pogodin ◽

Alexey A. Lagunin ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Interactions ◽

Cytochromes P450 ◽

Investigational Drug ◽

Web Resource ◽

Average Accuracy ◽

Structural Formulas ◽

Cytochrome P450 Isoforms ◽

Leave One Out ◽

Important Drug

Drug–drug interactions (DDIs) can cause drug toxicities, reduced pharmacological effects, and adverse drug reactions. Studies aiming to determine the possible DDIs for an investigational drug are part of the drug discovery and development process and include an assessment of the DDIs potential mediated by inhibition or induction of the most important drug-metabolizing cytochrome P450 isoforms. Our study was dedicated to creating a computer model for prediction of the DDIs mediated by the seven most important P450 cytochromes: CYP1A2, CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. For the creation of structure–activity relationship (SAR) models that predict metabolism-mediated DDIs for pairs of molecules, we applied the Prediction of Activity Spectra for Substances (PASS) software and Pairs of Substances Multilevel Neighborhoods of Atoms (PoSMNA) descriptors calculated based on structural formulas. About 2500 records on DDIs mediated by these cytochromes were used as a training set. Prediction can be carried out both for known drugs and for new, not-yet-synthesized substances. The average accuracy of the prediction of DDIs mediated by various isoforms of cytochrome P450 estimated by leave-one-out cross-validation (LOO CV) procedures was about 0.92. The SAR models created are publicly available as a web resource and provide predictions of DDIs mediated by the most important cytochromes P450.

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Novel Substituted Pyridinyl Imidazoles as Potent Anticytokine Agents with Low Activity against Hepatic Cytochrome P450 Enzymes

Journal of Medicinal Chemistry ◽

10.1021/jm030766k ◽

2003 ◽

Vol 46 (15) ◽

pp. 3230-3244 ◽

Cited By ~ 80

Author(s):

Stefan A. Laufer ◽

Gerd K. Wagner ◽

Dunja A. Kotschenreuther ◽

W. Albrecht

Keyword(s):

Cytochrome P450 ◽

Cytochrome P450 Enzymes ◽

Low Activity ◽

Hepatic Cytochrome

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A Novel Thermostable Cytochrome P450 from Sequence-Based Metagenomics of Binh Chau Hot Spring as a Promising Catalyst for Testosterone Conversion

Catalysts ◽

10.3390/catal10091083 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1083 ◽

Cited By ~ 1

Author(s):

Kim-Thoa Nguyen ◽

Ngọc-Lan Nguyen ◽

Nguyen Van Tung ◽

Huy Hoang Nguyen ◽

Mohammed Milhim ◽

...

Keyword(s):

Cytochrome P450 ◽

Retinoic Acid ◽

Amino Acid Sequence Identity ◽

Hot Spring ◽

Cytochromes P450 ◽

Reading Frame ◽

Redox Partner ◽

Redox Partners ◽

Identification And Characterization ◽

Low Activity

Biotechnological applications of cytochromes P450 show difficulties, such as low activity, thermal and/or solvent instability, narrow substrate specificity and redox partner dependence. In an attempt to overcome these limitations, an exploitation of novel thermophilic P450 enzymes from nature via uncultured approaches is desirable due to their great advantages that can resolve nearly all mentioned impediments. From the metagenomics library of the Binh Chau hot spring, an open reading frame (ORF) encoding a thermostable cytochrome P450—designated as P450-T3—which shared 66.6% amino acid sequence identity with CYP109C2 of Sorangium cellulosum So ce56 was selected for further identification and characterization. The ORF was synthesized artificially and heterologously expressed in Escherichia coli C43(DE3) using the pET17b system. The purified enzyme had a molecular weight of approximately 43 kDa. The melting temperature of the purified enzyme was 76.2 °C and its apparent half-life at 60 °C was 38.7 min. Redox partner screening revealed that P450-T3 was reduced well by the mammalian AdR-Adx4-108 and the yeast Arh1-Etp1 redox partners. Lauric acid, palmitic acid, embelin, retinoic acid (all-trans) and retinoic acid (13-cis) demonstrated binding to P450-T3. Interestingly, P450-T3 also bound and converted testosterone. Overall, P450-T3 might become a good candidate for biocatalytic applications on a larger scale.

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Potential Drug Interactions between Recombinant Interleukin-2 and Direct Oral Anticoagulants: Indirect Evidence from In Vivo Animal Studies

Hämostaseologie ◽

10.1055/a-1120-4064 ◽

2020 ◽

Vol 40 (05) ◽

pp. 679-686

Author(s):

Seyed Hamidreza Mahmoudpour ◽

Luca Valerio ◽

Jonathan Douxfils ◽

Charles E. Mahan ◽

Marius Jankowski ◽

...

Keyword(s):

Systematic Review ◽

Cytochrome P450 ◽

Drug Interactions ◽

Animal Studies ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Interleukin 2 ◽

Coronary Syndrome ◽

Recombinant Interleukin 2 ◽

Hepatic Cytochrome

AbstractRecombinant interleukin-2 (rIL-2) is indicated for metastatic renal cell carcinoma and melanoma. Over recent years low-dose rIL-2 has been studied for the treatment of autoimmune diseases and acute coronary syndrome because of its ability to expand and activate T regulatory (Treg) cells. However, several medical conditions potentially benefiting from rIL-2 administrations are characterized by an intrinsic prothrombotic risk, thus requiring concurrent anticoagulation. In our systematic review of the literature, we investigated the potential for drug interactions between oral anticoagulants and rIL-2 by assessing the influence of rIL-2 administration on transporters and cytochromes determining the pharmacokinetics of (direct) oral anticoagulants. We extracted data from 12 studies, consisting of 11 animal studies and one study in humans. Eight studies investigated the pharmacokinetics of P-glycoprotein (P-gp) substrates and reported that the intraperitoneal rIL-2 administration may inhibit intestinal P-gp. Four studies on hepatic cytochrome P450 yielded conflicting results. The only human study included in this systematic review concluded that rIL-2 suppresses the hepatic cytochrome P450, but only if given at higher doses. Based on the results from animal studies, the co-administration of rIL-2 and dabigatran etexilate, a substrate of intestinal P-gp, may lead to higher dabigatran plasma concentrations and bioavailability. Human studies should confirm whether this potential interaction is clinically relevant.

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