Cytochrome P450 2A6 and other human P450 enzymes in the oxidation of flavone and flavanone

Kakimoto, Kensaku; Murayama, Norie; Takenaka, Shigeo; Nagayoshi, Haruna; Lim, Young-Ran; Kim, Vitchan; Kim, Donghak; Yamazaki, Hiroshi; Komori, Masaharu; Guengerich, F. Peter; Shimada, Tsutomu

doi:10.1080/00498254.2018.1426133

Cited by 17 publications

(40 citation statements)

References 63 publications

(91 reference statements)

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“…Flavonoids generally have low bioavailability due to interactions with digestive enzymes and intestinal microorganisms [ 18 ]. Flavanones were metabolized to flavone by CYP2A6 and CYP2A13 in the liver [ 19 ] and mainly excreted in urine within 4–8 h [ 20 ]. In this study, the compounds were intravenously administered to avoid intestinal interactions; therefore, the toxicity would be observed in nonmetabolized forms of TH011 and TH002 .…”

Section: Resultsmentioning

confidence: 99%

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Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity

et al. 2020

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Dengue infection is one of the most deleterious public health concerns for two-billion world population being at risk. Plasma leakage, hemorrhage, and shock in severe cases were caused by immunological derangement from secondary heterotypic infection. Flavanone, commonly found in medicinal plants, previously showed potential as anti-dengue inhibitors for its direct antiviral effects and suppressing the pro-inflammatory cytokine from dengue immunopathogenesis. Here, we chemically modified flavanones, pinocembrin and pinostrobin, by halogenation and characterized them as potential dengue 2 inhibitors and performed toxicity tests in human-derived cells and in vivo animal model. Dibromopinocembrin and dibromopinostrobin inhibited dengue serotype 2 at the EC50s of 2.0640 ± 0.7537 and 5.8567 ± 0.5074 µM with at the CC50s of 67.2082 ± 0.9731 and >100 µM, respectively. Both of the compounds also showed minimal toxicity against adult C57BL/6 mice assessed by ALT and Cr levels in day one, three, and eight post-intravenous administration. Computational studies suggested the potential target be likely the NS5 methyltransferase at SAM-binding pocket. Taken together, these two brominated flavanones are potential leads for further drug discovery investigation.

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Section: Resultsmentioning

confidence: 99%

“…in the rat (10 mg, single dose) and 47 min. in human (20 mg, iv drip) [ 32 ], mainly by CYP2A6 and CYP2A13 metabolism [ 19 ] and renal clearance. Therefore, further in vivo efficacy should include the multiple doses of administration in order to maintain the therapeutic level during viremia or febrile phase.…”

Section: Discussionmentioning

confidence: 99%

Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity

et al. 2020

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“…Biological activities of flavonoids vary with the number and substitution positions of hydroxyl and/or methoxy groups [54]. Kakimoto et al [55] showed that CYP2A6 and other human P450s play important roles in the metabolism of flavone and flavanones. According to Bojic et al [56].…”

Section: Bioavailability and Drug Interactionsmentioning

confidence: 99%

Dietary Flavonoids Interaction with CREB-BDNF Pathway: An Unconventional Approach for Comprehensive Management of Epilepsy

Sharma

Kumar

Singh

2019

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cAMP response element binding protein (CREB) is a key transcriptional regulator that regulates the transcription of genes related with neuronal differentiation, synaptic plasticity, learning and memory. Brain derived neurotrophic factor (BDNF), is a CREB dependent gene which plays a pivotal role in the pathogenesis of epilepsy and central comorbid conditions associated with epilepsy. However, the beneficial or detrimental consequences of CREB-BDNF activation on the induction and/or progression of seizures depend specifically on the region of brain involved and the time of activation. The bioactive molecules that alter the activity of CREB in a way to have specialized effects in different brain regions and neural circuits involved could potentially be utilized for therapeutic purposes. Flavonoids are the polyphenolic compounds which lead to phosphorylation of CREB in the hippocampus, followed by increase in extracellular signal regulated kinase (ERK) and BDNF. Several members of flavonoid family have also showed suppression of epileptic seizures via interaction with CREB/BDNF pathway. Moreover, epilepsy is often accompanied by a number of behavioural and psychological comorbid conditions that further gets aggravated by the use of conventional antiepileptic drug therapy. Multiple studies have also supported the beneficial effects of flavonoids in cognitive and memory impairments by upregulation of CREB-BDNF pathway. The current review is an attempt to collate the available preclinical and clinical studies to establish the therapeutic potential of various dietary flavonoids in comprehensive management of epilepsy with relation to CREB-BDNF pathway.

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“…difficulty of their extraction from plant sources or the necessity for complicated procedures to obtain them synthetically. Several papers have reported flavonoid hydroxylations catalyzed by P450s from mammals [54], plants [55], bacteria [56] or fungi [57]. To the best of our knowledge, production of 3-hydroxyflavanone with flavanone as substrate was only reported recently, in a whole-cell system expressing CYP110E1 from Nostoc sp.…”

Section: Biosynthesis Of Differently Hydroxylated Flavonoids Is Of Himentioning

confidence: 99%

Structural insights into oxidation of medium-chain fatty acids and flavanone by myxobacterial cytochrome P450 CYP267B1

Jozwik

Litzenburger

Khatri

et al. 2018

Biochemical Journal

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Oxidative biocatalytic reactions performed by cytochrome P450 enzymes (P450s) are of high interest for the chemical and pharmaceutical industries. CYP267B1 is a P450 enzyme from myxobacterium So ce56 displaying a broad substrate scope. In this work, a search for new substrates was performed, combined with product characterization and a structural analysis of substrate-bound complexes using X-ray crystallography and computational docking. The results demonstrate the ability of CYP267B1 to perform in-chain hydroxylations of medium-chain saturated fatty acids (decanoic acid, dodecanoic acid and tetradecanoic acid) and a regioselective hydroxylation of flavanone. The fatty acids are mono-hydroxylated at different in-chain positions, with decanoic acid displaying the highest regioselectivity towardsω-3 hydroxylation. Flavanone is preferably oxidized to 3-hydroxyflavanone. High-resolution crystal structures of CYP267B1 revealed a very spacious active site pocket, similarly to other P450s capable of converting macrocyclic compounds. The pocket becomes more constricted near to the heme and is closed off from solvent by residues of the F and G helices and the B-C loop. The crystal structure of the tetradecanoic acid-bound complex displays the fatty acid bound near to the heme, but in a nonproductive conformation. Molecular docking allowed modeling of the productive binding modes for the four investigated fatty acids and flavanone, as well as of two substrates identified in a previous study (diclofenac and ibuprofen), explaining the observed product profiles. The obtained structures of CYP267B1 thus serve as a valuable prediction tool for substrate hydroxylations by this highly versatile enzyme and will encourage future selectivity changes by rational protein engineering.

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Cytochrome P450 2A6 and other human P450 enzymes in the oxidation of flavone and flavanone

Cited by 17 publications

References 63 publications

Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity

Dibromopinocembrin and Dibromopinostrobin Are Potential Anti-Dengue Leads with Mild Animal Toxicity

Dietary Flavonoids Interaction with CREB-BDNF Pathway: An Unconventional Approach for Comprehensive Management of Epilepsy

Structural insights into oxidation of medium-chain fatty acids and flavanone by myxobacterial cytochrome P450 CYP267B1

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