Identification of Inhibitory Component in Cinnamon —O-Methoxycinnamaldehyde Inhibits CYP1A2 and CYP2E1—

doi:10.2133/dmpk.17.229

Drug Metabolism and Pharmacokinetics

Volume 17, Issue 3, 2002, Pages 229-236

https://doi.org/10.2133/dmpk.17.229 Get rights and content

Summary:

The Cinnamomi Cortex and Ephedra Herba were found to more strongly inhibit aminopyrine N-demethylation in rat liver microsomes compared to other constituents included in Sho-seiryu-to. The component inhibiting drug oxidations catalyzed by CYP1A2 and CYP2E1 was isolated from Cinnamomi Cortex, and was identified as o-methoxycinnamaldehyde (OMCA). When phenacetin and 4-nitrophenol were used as probe substrates for CYP1A2 and CYP2E1, respectively, the OMCA was shown to be a competitive inhibitor against CYP1A2 while it was a mixed type inhibitor against CYP2E1. The inhibitory effect of OMCA on 4-nitrophenol 2-hydroxylation (K_i = 6.3 μΜ) was somewhat potent compared to that observed on phenacetin O-deethylation (K_i = 13.7 μΜ) in rat liver microsomes.

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Cited by (20)

4-Methoxycinnamaldehyde inhibited human respiratory syncytial virus in a human larynx carcinoma cell line
2009, Phytomedicine
4-Methoxycinnamaldehyde, an active constituent of Agastache rugosa, was examined for its cytoprotective activity against RSV by XTT method in human larynx carcinoma cell line. 4-Methoxycinnamaldehyde could effectively inhibit cytopathic effect of RSV (p<0.0001) with an estimated IC₅₀ of 0.055 μg/ml and a selectivity index (SI) of 898.2. 4-Methoxycinnamaldehyde (0.03 μg/ml) could inhibit viral entrance by interfering viral attachment (IC₅₀ of 0.06 μg/ml; p<0.0001) and internalization (IC₅₀ of 0.01 μg/ml; p<0.0001). 4-Methoxycinnamaldehyde significantly increased the basal production of IFN (p=0.0015), but not the virus-induced IFN production. Therefore, its cytoprotective activity against RSV was not mediated by interferon. In conclusion, 4-methoxycinnamaldehyde might be helpful to manage the disease induced by RSV infection.
Aldehydic components of Cinnamon bark extract suppresses RANKL-induced osteoclastogenesis through NFATc1 downregulation
2008, Bioorganic and Medicinal Chemistry
Several major bone diseases are directly attributable to bone loss, including osteoporosis, bone metastasis, and rheumatoid arthritis. The nuclear factor of activated T cell 1 (NFATc1), a transcription factor, has recently been shown to play an essential role in osteoclastogenesis. In this study, we found that of several herbs, Cinnamomum zeylanicum (C. zeylanicum) exhibited the strong inhibitory effects on osteoclastogenesis and that its mechanism of action involves the suppression of NFATc1-mediated signal transduction. C. zeylanicum dose-dependently inhibited osteoclast-like cell formation at concentrations of 12.5-50 μg/ml without affecting cell viability. Resorption pit assays have shown that C. zeylanicum also inhibits the bone-resorbing activity of mature osteoclasts. Treatment with C. zeylanicum inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced NFATc1 and c-fos expression. Additionally, C. zeylanicum moderately inhibited phosphorylation of IκB-α, suggesting that the c-fos/NFATc1 pathway, rather than the nuclear factor-κB (NF-κB) pathway, is the primary target of C. zeylanicum during RANKL-induced osteoclastogenesis. Using an HPLC-DAD system, we identified three major peaks for four characteristic components in the C. zeylanicum extract and identified an unknown peak as 2-methoxycinnamaldehyde via HPLC and a 2D-COSY ¹H NMR study. We identified cinnamaldehyde and 2-methoxycinnamaldehyde as active components reducing osteoclast-like cell formation and inhibiting NFATc1 expression. Notably, in a resorption pit assay, 2-methoxycinnamaldehyde exhibited remarkable inhibition rates of 95% at 2 μM on bone resorption. In summary, this study points to the conclusion that C. zeylanicum inhibits RANKL-induced osteoclastogenesis. This finding raises prospects for the development of a novel approach in the treatment of osteopenic disease.
Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes
2007, Archives of Biochemistry and Biophysics
Citation Excerpt :
Our extraction procedure removes a great majority of the toxic lipid-soluble compounds from cinnamon bark [8]. However, the inhibition of IRβ level in 3T3-L1 adipocytes by high concentrations of the unpurified extract may suggest that the crude extract still contains minor inhibitory compounds such as cinnamaldehyde [37]. Further analyses suggest that the reduction of IRβ level in high concentrations of CE treatment might not be due to general toxicity of the cinnamon compounds because the cells were grown normally by judging the cell morphology and the total soluble protein content but probably due to feedback inhibition of specific metabolic and/or signal transduction pathways by high concentrations of cinnamon compounds.
Cinnamon improves glucose and lipid profiles of people with type 2 diabetes. Water-soluble cinnamon extract (CE) and HPLC-purified cinnamon polyphenols (CP) with doubly linked procyanidin type-A polymers display insulin-like activity. The objective of this study was to investigate the effects of cinnamon on the protein and mRNA levels of insulin receptor (IR), glucose transporter 4 (GLUT4), and tristetraprolin (TTP/ZFP36) in mouse 3T3-L1 adipocytes. Immunoblotting showed that CP increased IRβ levels and that both CE and CP increased GLUT4 and TTP levels in the adipocytes. Quantitative real-time PCR indicated that CE (100 μg/ml) rapidly increased TTP mRNA levels by approximately 6-fold in the adipocytes. CE at higher concentrations decreased IRβ protein and IR mRNA levels, and its effect on GLUT4 mRNA levels exhibited a biphasic pattern in the adipocytes. These results suggest that cinnamon exhibits the potential to increase the amount of proteins involved in insulin signaling, glucose transport, and anti-inflammatory/anti-angiogenesis response.
Mechanism-based inhibition of CYP3A4 and CYP2D6 by Indonesian medicinal plants
2006, Journal of Ethnopharmacology
Thirty samples of Indonesian medicinal plants were tested for their mechanism-based inhibition on cytochrome P450 3A4 (CYP3A4) and CYP2D6 via erythromycin N-demethylation and dextromethorphan O-demethylation activities in human liver microsomes. From screening with 0 and 20 min preincubation at 0.5 mg/ml of methanol extracts, five plants (Cinnamomum burmani bark, Foeniculum vulgare seed, Strychnos ligustrina wood, Tinospora crispa stem, and Zingiber cassumunar rhizome) showed more than 30% increase of CYP3A4 inhibition, while three (Alpinia galanga rhizome, Melaleuca leucadendron leaf, and Piper nigrum fruit) showed more than 30% increase of CYP2D6 inhibition. In these eight plants, Foeniculum vulgare seed, Cinnamomum burmani bark, and Strychnos ligustrina wood showed time-dependent inhibition on CYP3A4 and Piper nigrum fruit and Melaleuca leucadendron leaf on CYP2D6. Among these, four plants other than Melaleuca leucadendron revealed NADPH-dependent inhibition. Thus, Foeniculum vulgare, Cinnamomum burmani, and Strychnos ligustrina should contain mechanism-based inhibitors on CYP3A4 and Piper nigrum contain that on CYP2D6.
CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants
2006, Phytomedicine
Thirty samples of Indonesian medicinal plants were analyzed for their capacity to inhibit in vitro metabolism by human cytochrome P450 3A4 (CYP3A4) and CYP2D6 with a radiometric assay. The MeOH-soluble fractions of 25 samples, prepared from water extracts, demonstrated inhibitory activity more than 50% on the metabolism mediated by CYP3A4, and 21 samples on the metabolism mediated by CYP2D6. Among the MeOH-soluble fractions, Piper nigrum leaf showed the highest inhibitory activity against CYP3A4 (91.7%), and Punica granatum against CYP2D6 (98.1%). The water extracts of which MeOH-soluble fraction showed inhibitory activity more than 70% were fractionated with EtOAc. From the EtOAc-soluble fractions, Curcuma heyneana (67.0%), Pi. cubeba (75.0%), Pi. nigrum fruit (84.0%), Pi. nigrum leaf (85.8%), and Zingiber aromaticum (75.3%) demonstrated inhibitory activity more than 50% on the metabolism mediated by CYP3A4, but only Pi. nigrum fruit (72.8%) and Pi. nigrum leaf (69.1%) showed strong inhibitory activity against CYP2D6. For samples that showed more than 70% inhibition, their IC₅₀ values were determined. The most potent inhibitory activity against CYP3A4 (IC₅₀ value of 25 μg/ml) was found for the extract of Pi. nigrum leaf, while that of Catharanthus roseus showed the most potent inhibitory effect against CYP2D6 (IC₅₀ value of 11 μg/ml). These results should indicate once more the possibility of potential medicinal plant–drug interactions.
Potential herb–drug interactions in the management of age-related cognitive dysfunction
2021, Pharmaceutics

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Drug Metabolism and Pharmacokinetics

Summary:

References (27)

Interaction of Hepericum perfortum (St. John's wort) with cyclosporin A metabolism in a patient after liver transplantation. J

Hepatology

The carbon monoxide-binding pigment of liver microsomes

J. Biol. Chem.

Protein measurement with the Folin phenol reagent

J. Biol. Chem.

A new cytochrome P450 form belonging to the CYP 2D in dog liver microsomes: purification, cDNA cloning, and enzyme characterization

Arch. Biochem. Biophys.

High-performance liquid chromatographic assay for 4-nitrophenol hydroxylation, a putative cytochrome P-450 2E1 activity, in human liver microsomes

J. Chromato.

High affinity phenacetin O-deethylase is catalysed specifically by cytochrome P450d (P4501A2) in the liver of the rat

Biochem. Pharmacol.

Varidation of 4-nitrophenol as an in vitro substrate probe for human liver CYP2E1 using cDNA expression and microsomal kinetic techniques

Biochem. Pharmacol.

Hepatic microsomal oxygenation of aldehydes to carboxylic acids

Biochem. Biophys. Res. Commun.

Protective effect of sodium L-malate, an active constituent isolated from Angelicae radix, on cis-diamminedichloroplatinum (Il)-induces toxic side effect

Chem. Pharm. Bull.

Effect of Ju-zen taiho-to in reducing the side effect of cisplatin

J. Trad. Med.

Protective effects of kampo medicines and baicalin against intestinal toxicity a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11) in rats

Jpn. J. Cancer. Res.

Grapefruit juice-drug interactions

Br. J. Clin. Phramcol.

Specific CYP 3A4 inhibitors in grapefruit juice: furanocoumarin dimers as components of drug interaction

Pharmacogenetics

Cited by (20)

4-Methoxycinnamaldehyde inhibited human respiratory syncytial virus in a human larynx carcinoma cell line

Aldehydic components of Cinnamon bark extract suppresses RANKL-induced osteoclastogenesis through NFATc1 downregulation

Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes

Mechanism-based inhibition of CYP3A4 and CYP2D6 by Indonesian medicinal plants

CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants

Potential herb–drug interactions in the management of age-related cognitive dysfunction

Regular ArticleIdentification of Inhibitory Component in Cinnamon —O-Methoxycinnamaldehyde Inhibits CYP1A2 and CYP2E1—

Summary:

Hepatology

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

J. Chromato.

Biochem. Pharmacol.

Biochem. Pharmacol.

Biochem. Biophys. Res. Commun.

Protective effect of sodium L-malate, an active constituent isolated from Angelicae radix, on cis-diamminedichloroplatinum (Il)-induces toxic side effect

Chem. Pharm. Bull.

Effect of Ju-zen taiho-to in reducing the side effect of cisplatin

J. Trad. Med.

Protective effects of kampo medicines and baicalin against intestinal toxicity a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11) in rats

Jpn. J. Cancer. Res.

Grapefruit juice-drug interactions

Br. J. Clin. Phramcol.

Specific CYP 3A4 inhibitors in grapefruit juice: furanocoumarin dimers as components of drug interaction

Pharmacogenetics

Regular Article
Identification of Inhibitory Component in Cinnamon —O-Methoxycinnamaldehyde Inhibits CYP1A2 and CYP2E1—