Oxidation and rearrangements of flavanones by mammalian cytochrome P450

Kagawa, Hitoshi; Ohta, Shigeru; Harigaya, Yoshihiro

doi:10.1080/00498250400005708

Cited by 18 publications

(12 citation statements)

References 28 publications

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“…2) (Breinholt et al 2002;Kagawa et al 2004). CYP1A1, CYP1A2 and CYP2B6 produce flavone, and CYP1A1 and CYP2B6 even produce isoflavone, from flavanone (Kagawa et al 2004).…”

Section: Non-plant P450s Catalyzing Flavonoid Metabolism and Catabolismmentioning

confidence: 95%

Cytochrome P450s in flavonoid metabolism

2006

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In this review, cytochrome P450s characterized at the molecular level catalyzing aromatic hydroxylations, aliphatic hydroxylations and skeleton formation in the flavonoid metabolism are surveyed. They are involved in the biosynthesis of anthocyanin pigments and condensed tannin (CYP75, flavonoid 3¢,5¢-hydroxylase and 3¢-hydroxylase), flavones [CYP93B, (2S)-flavanone 2-hydroxylase and flavone synthase II], and leguminous isoflavonoid phytoalexins [CYP71D9, flavonoid 6-hydroxylase; CYP81E, isoflavone 2¢-hydroxylase and 3¢-hydroxylase; CYP93A, 3,9-dihydroxypterocarpan 6a-hydroxylase; CYP93C, 2-hydroxyisoflavanone synthase (IFS)]. Other P450s of the flavonoid metabolism include methylenedioxy bridge forming enzyme, cyclases producing glyceollins, flavonol 6-hydroxylase and 8-dimethylallylnaringenin 2¢-hydroxylase. Mechanistic studies on the unusual aryl migration by CYP93C, regulation of IFS expression in plant organs and its biotechnological applications are introduced, and flavonoid metabolisms by non-plant P450s are also briefly discussed.

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“…2) (Breinholt et al 2002;Kagawa et al 2004). CYP1A1, CYP1A2 and CYP2B6 produce flavone, and CYP1A1 and CYP2B6 even produce isoflavone, from flavanone (Kagawa et al 2004).…”

Section: Non-plant P450s Catalyzing Flavonoid Metabolism and Catabolismmentioning

confidence: 95%

Cytochrome P450s in flavonoid metabolism

2006

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“…16) In order to identify other metabolic monohydroxyflavanones, we have now developed procedures to synthetically produce these compounds and to identify them by GC-MS analysis.…”

Section: )mentioning

confidence: 99%

“…10) Recently, two interesting pharmacological properties of flavonoids have been reported. 1) The polymethoxyflavone, tangeretin, protects against the development of experimentally-induced Parkinson's disease in rats.11) 2) Other polymethoxyflavones inhibit the cellular excretion of certain drugs-a process mediated by P-glycoprotein.12,13) Cytochrome P450s can remove a flavonoid C-4Ј methyl and can add a hydroxyl at the C-3Ј position.14,15) To understand the diverse pharmacological effects of dietary flavonoids, their metabolic pathways must be known.A previous study of ours 16) showed that both rat and human cytochrome P450s convert flavanones to the corresponding 2,3-trans-flavanonols and flavones; whereas, only the human enzyme can convert the flavanone to isoflavone. We also recently reported a procedure for the specific deuteration of flavanones.…”

mentioning

confidence: 99%

“…A previous study of ours 16) showed that both rat and human cytochrome P450s convert flavanones to the corresponding 2,3-trans-flavanonols and flavones; whereas, only the human enzyme can convert the flavanone to isoflavone. We also recently reported a procedure for the specific deuteration of flavanones.…”

mentioning

confidence: 99%

“…20,21) Consequently, only those compounds could be unquestionably identified as P450 metabolic products during our previous study. 16) In order to identify other metabolic monohydroxyflavanones, we have now developed procedures to synthetically produce these compounds and to identify them by GC-MS analysis.…”

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confidence: 99%

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Preparative Monohydroxyflavanone Syntheses and a Protocol for Gas Chromatography-Mass Spectrometry Analysis of Monohydroxyflavanones

Kagawa

Shigematsu

Ohta

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Flavonoids are phenolic compounds found in most plants.Since flavonoids are naturally present in fruits, vegetables, and tea, they are an integral part of the human diet.1) Ingested flavonoids are absorbed by the gastrointestinal tract and have been found in blood plasma.2) Flavonoids possess various biological and pharmacological properties, such as antioxidant activity, 3) anti-HIV-1 activity, 4) and anti-inflammatory activity. 5) They seem to protect against cancer onset, 6) vascular dementia, 7) and coronary heart disease-related deaths. 8)Flavonoids also modulate the activities of enzymes that metabolize drugs. 9) Flavonoids form the largest class of phytoestrogens known. The binding affinity of a flavonoid for the estrogen receptor primarily depends on the positions of Aand C-ring hydroxyl groups. 10) Recently, two interesting pharmacological properties of flavonoids have been reported. 1) The polymethoxyflavone, tangeretin, protects against the development of experimentally-induced Parkinson's disease in rats.11) 2) Other polymethoxyflavones inhibit the cellular excretion of certain drugs-a process mediated by P-glycoprotein.12,13) Cytochrome P450s can remove a flavonoid C-4Ј methyl and can add a hydroxyl at the C-3Ј position.14,15) To understand the diverse pharmacological effects of dietary flavonoids, their metabolic pathways must be known.A previous study of ours 16) showed that both rat and human cytochrome P450s convert flavanones to the corresponding 2,3-trans-flavanonols and flavones; whereas, only the human enzyme can convert the flavanone to isoflavone. We also recently reported a procedure for the specific deuteration of flavanones.17) With these deuterated flavanones as substrates, we determined that, most likely, the initial step in flavanone P450-catalyzed metabolism is abstraction of a hydrogen radical from the C-2 or -3 position of the flavanone skeleton.After rats received flavanone via a stomach tube, the most common urinary metabolites found were those with the C-4 ketone reduced and those with hydroxyls added at positions C-3 and C-6.18) Another P450 metabolic study found that aromatic hydroxylation products, flavones, unusual quinoltype oxidation products, chromone derivatives, and flavan-4-ol derivatives were produced when several different flavanones were substrates.19) Therefore, although all flavonoids have a common three-ring skeleton, it appears that ring substituents determine the metabolic fate of a specific substrate.If demethylated and hydroxylated flavonoid P450 metabolic products, amongst others, are to be unequivocally characterized, their physical properties must be compared with known standards. Previously, we reported a synthetic procedure for (Ϯ)-2,3-trans-flavanonols, which are hydroxylated at the C-3 position.20,21) Consequently, only those compounds could be unquestionably identified as P450 metabolic products during our previous study. 16) In order to identify other metabolic monohydroxyflavanones, we have now developed procedures to synthetically produce these co...

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Metabolism of 7‐ethoxycoumarin, safrole, flavanone and hydroxyflavanone by cytochrome P450 2A6 variants

Uno

Obe

Ogura

et al. 2012

Biopharm & Drug Disp

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CYP 2A6 is a human enzyme that metabolizes many xenobiotics including coumarin, indole, nicotine and carcinogenic nitrosamines. The gene for CYP2A6 is polymorphic. There are few data available to clarify the relationship between P450 genetic variants and the metabolism of materials in food. The CYP 2A6 wild-type protein and 13 mutants (CYP2A6.1, CYP2A6.2, CYP2A6.5, CYP2A6.6, CYP2A6.7, CYP2A6.8, CYP2A6.11, CYP2A6.15, CYP2A6.16, CYP2A6.17, CYP2A6.18, CYP2A6.21, CYP2A6.23 and CYP2A6.25) were co-expressed with NADPH-cytochrome P450 reductase in E. coli. The hydroxylase activities toward 7-ethoxycoumarin, coumarin, safrole, flavanone and hydroxyflavanone were examined. Ten types of CYP2A6 variants except for CYP2A6.2, CYP2A6.5 and CYP2A6.6 showed Soret peaks (450 nm) typical of P450 in the reduced CO-difference spectra and had 7-ethoxycoumarin O-deethylase activities. CYP2A6.15 and CYP2A6.18 showed higher activities for safrole 1'-hydroxylation than CYP2A6.1. CYP2A6.25 and CYP2A6.7 had lower safrole 1'-hydroxylase activities. CYP2A6.7 had lower flavanone 6- and 2'-hydroxylase activities, whereas CYP2A6.25 had higher 6-hydroxylase activity and lower 2'-hydroxylase activity. Hydroxyflavanone was metabolized by CYP2A6.25, but was not metabolized by wild-type CYP2A6.1. These results indicate that CYP2A6.25 possessed new substrate specificity toward flavonoids.

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Oxidation and rearrangements of flavanones by mammalian cytochrome P450

Cited by 18 publications

References 28 publications

Cytochrome P450s in flavonoid metabolism

Cytochrome P450s in flavonoid metabolism

Preparative Monohydroxyflavanone Syntheses and a Protocol for Gas Chromatography-Mass Spectrometry Analysis of Monohydroxyflavanones

Metabolism of 7‐ethoxycoumarin, safrole, flavanone and hydroxyflavanone by cytochrome P450 2A6 variants

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