Dehydrodiisoeugenol

Planta Med. 2011 Oct;77(15):1712-7.

Metabolism of the lignan dehydrodiisoeugenol in rats.[Pubmed: 21544774]

Dehydrodiisoeugenol (DDIE), a major active lignan from the seed and aril of the fruit of Myristica fragrans Houtt., functions as a potential anti-inflammatory agent by inhibiting lipopolysaccharide-stimulated nuclear factor kappa B activation and cyclooxygenase-2 expression in macrophages. However, the metabolism of DDIE remains unknown.
METHODS AND RESULTS:
This report describes the metabolic fate of DDIE in liver microsomes, urine, and feces of rats treated with DDIE. DDIE metabolites were isolated by sequential column chromatography and high-performance liquid chromatography from liver microsomes incubations, urine, and feces. Nine metabolites ( M-1 to M-9), including 5 new metabolites, were determined spectroscopically using ultra-violet (UV), mass spectrometry (MS), nuclear magnetic resonance (NMR), and circular dichroism (CD). Analysis of the isolated metabolites showed that DDIE undergoes four major pathways of metabolism in the rat: oxidation (including hydroxylation, hydroformylation, and acetylation), demethylation, ring-opening, and dehydrogenation. In contrast to the metabolites from liver microsomes, the major metabolites In vivo were generated from DDIE by multiple metabolic reactions.
CONCLUSIONS:
Given these results, we describe a metabolic pathway for DDIE in the rat that gives insight into the metabolism of DDIE and the mechanism of DDIE bioactivity in humans.

J Pharm Biomed Anal . 2017 Oct 25;145:725-733.

Metabolic profiling of dehydrodiisoeugenol using xenobiotic metabolomics[Pubmed: 28806569]

Abstract Dehydrodiisoeugenol (DDIE), a representative and major benzofuran-type neolignan in Myristica fragrans Houtt., shows anti-inflammatory and anti-bacterial actions. In order to better understand its pharmacological properties, xenobiotic metabolomics was used to determine the metabolic map of DDIE and its influence on endogenous metabolites. Total thirteen metabolites of DDIE were identified through in vivo and in vitro metabolism, and seven of them were reported for the first time in the present study. The identity of DDIE metabolites was achieved by comparison of the MS/MS fragmentation pattern with DDIE using ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI- QTOFMS). Demethylation and ring-opening reaction were the major metabolic pathways for in vivo metabolism of DDIE. Recombinant cytochrome P450s (CYPs) screening revealed that CYP1A1 is a primary enzyme contributing to the formation of metabolites D1-D4. More importantly, the levels of two endogenous metabolites 2,8-dihydroxyquinoline and its glucuronide were significantly elevated in mouse urine after DDIE exposure, which explains in part its modulatory effects on gut microbiota. Taken together, these data contribute to the understanding of the disposition and pharmacological activities of DDIE in vivo. Keywords: Dehydrodiisoeugenol; Metabolic profiling; UPLC-ESI-QTOFMS; Xenobiotic metabolomics.

Arch Biochem Biophys. 2005 Feb 15;434(2):326-32.

Dehydrodiisoeugenol, an isoeugenol dimer, inhibits lipopolysaccharide-stimulated nuclear factor kappa B activation and cyclooxygenase-2 expression in macrophages.[Pubmed: 15639233]

o-Methoxyphenols such as eugenol and isoeugenol exhibit anti-oxidant and anti-inflammatory activities, but at higher concentrations act as oxidants and potent allergens.
METHODS AND RESULTS:
We recently demonstrated the eugenol dimer bis-eugenol to be an efficient inhibitor of lipopolysaccharide (LPS)-induced inflammatory cytokine expression in macrophages without cytotoxicity. This result suggested that dimer compound of o-methoxyphenols may possess anti-inflammatory activity. Thus, we further synthesized Dehydrodiisoeugenol and alpha-diisoeugenol from isoeugenols, and investigated whether these dimers could inhibit LPS-stimulated nuclear factor kappa B (NF-kappaB) activation and cyclooxygenase (COX)-2 gene expression, both of which are closely involved in inflammation and mutagenesis. The expression of the COX-2 gene was strongly inhibited by Dehydrodiisoeugenol in RAW264.7 murine macrophages stimulated with LPS. In contrast, isoeugenol and alpha-diisoeugenol did not inhibit it. Dehydrodiisoeugenol also significantly inhibited LPS-stimulated phosphorylation-dependent proteolysis of inhibitor kappaB-alpha and transcriptional activity of NF-kappaB in the cells.
CONCLUSIONS:
These findings suggest that Dehydrodiisoeugenol acts as a potent anti-inflammatory agent.

Fitoterapia. 2013 Jan;84:47-53.

Cerebral nuclei distribution study of dehydrodiisoeugenol as an anxiogenic agent determined by RP-HPLC.[Pubmed: 23059843]

METHODS AND RESULTS:
A sensitive RP-HPLC-DAD method was established to quantify Dehydrodiisoeugenol (DDIE) in rat cerebral nuclei. The assay procedure involved one-step extraction of Dehydrodiisoeugenol and daidzein, as an internal standard, from rat plasma and various cerebral nuclei with ethyl acetate. Chromatographic separation was performed on a Diamonsil™ ODS C(18) column with methanol-water (81:19, v/v) as a mobile phase. The UV absorbance of the samples was measured at the wavelength of 270nm. The analysis method was proved to be precise and accurate at linearity ranges in plasma and each cerebral nucleus with correlation coefficients of ≥0.9971. The results indicated that the method established was successfully applied to cerebral nuclei distribution study of Dehydrodiisoeugenol after intravenous administration at a single dose of 40mg/kg to rat. Dehydrodiisoeugenol showed high concentration in all of cerebral nuclei at 8min, which indicated that Dehydrodiisoeugenol could cross the blood-brain barrier rapidly and might be one of the main bioactive substances of nutmeg.
CONCLUSIONS:
The results provide fundamental data for evaluating the effects of Dehydrodiisoeugenol on the central nervous system and to be developed into an effective anxiogenic agent.