Biotransformation of Plant Secondary Metabolite Decursin by Mycobacterium sp. PYR1001

The aim of this study is to investigate and compare the metabolic rate and profiles of pyranocoumarin isomers decursin and decursinol angelate using liver microsomes from humans and rodents, and to characterize the major metabolites of decursin and decursinol angelate in human liver microsomal incubations using LC-MS/MS. First, we conducted liver microsomal incubations of decursin and decursinol angelate in the presence or absence of NADPH. We found that in the absence of NADPH, decursin was efficiently hydrolyzed to decursinol by hepatic esterase(s), but decursinol angelate was not. In contrast, formation of decursinol from decursinol angelate was mediated mainly by cytochrome P450(s). Second, we measured the metabolic rate of decursin and decursinol angelate in liver S9 fractions from mice and humans. We found that human liver S9 fractions metabolized both decursin and decursinol angelate more slowly than those of the mouse. Third, we characterized the major metabolites of decursin and decursinol angelate from human liver microsomes incubations using HPLC-UV and LC-MS/MS methods and assessed the in vivo metabolites in mouse plasma from a one-dose PK study. Decursin and decursinol angelate have different metabolite profiles. Nine metabolites of decursin and nine metabolites of decursinol angelate were identified in human liver microsome incubations besides decursinol using a hybrid triple quadruple linear ion trap LC-MS/MS system, and many of them were later verified to be also present in plasma samples from rodent PK studies.

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confidence: 99%

In Vitro Metabolism of Pyranocoumarin Isomers Decursin and Decursinol Angelate by Liver Microsomes from Man and Rodents

Zhang

Xing

et al. 2013

“…Angelica gigas roots are among the most frequently used natural products in traditional Oriental herbal medicine and dietary supplements (A. gigas Nakai, Apiaceae). They are administered orally, used as a sedative or tonic agent [1][2][3] and marketed as a functional food for womenʼs health care in Europe and the United States [4][5]. Several coumarin derivatives have been isolated from this plant as bioactive compounds [6].…”

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confidence: 99%

“…However, little is known about the systemic exposure of decursin after administration because the pharmacokinetics of decursin has not been characterized well in vivo as compared to its in vitro pharmacological activity. The only exception is the observation that decursin may be metabolized to decursinol which is also pharmacologically active [5,18,19]. Decursinol has as well various pharmacological activities, including analgesic, serotonergic, antiangiogenic, and anticancer effects [20][21][22][23].…”

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confidence: 99%

First-pass Metabolism of Decursin, a Bioactive Compound of Angelica gigas, in Rats

Park

Kim

et al. 2012

Decursin is considered the major bioactive compound of Angelica gigas roots, a popular Oriental herb and dietary supplement. In this study, the pharmacokinetics of decursin and its active metabolite, decursinol, were evaluated after the administration of decursin in rats. The plasma concentration of decursin decreased rapidly, with an initial half-life of 0.05 h. It was not detectable at 1 h after intravenous administration at an area under the plasma concentration-time curve of 1.20 µg · mL-1·h, whereas the concentration of decursinol increased rapidly reaching a maximum concentration of 2.48 µg · mL-1 at the time to maximum plasma concentration of 0.25 h and an area under the plasma concentration-time curve of 5.23 µg · mL-1·h. Interestingly, after oral administration of decursin, only decursinol was present in plasma, suggesting an extensive hepatic first-pass metabolism of decursin. The extremely low bioavailability of decursin after its administration via the hepatic portal vein (the fraction of dose escaping first-pass elimination in the liver, FH = 0.11) is indicative of extensive hepatic first-pass metabolism of decursin, which was confirmed by a tissue distribution study. These findings suggest that decursin is not directly associated with the bioactivity of A. gigas and that it may work as a type of natural prodrug of decursinol.

“…This paper identified the esterase activity of Mycobacterium sp. PYR1001, which was able to convert decursin to decursinol, but DA was totally resistant to this conversion [26]. Detailed studies using pure decursin and DA to elucidate their in vivo pharmacokinetic behaviors are needed for future studies.…”

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confidence: 99%

Quantitative Determination of Decursin, Decursinol Angelate, and Decursinol in Mouse Plasma and Tumor Tissue Using Liquid-Liquid Extraction and HPLC

Li¹,

Zhang²,

Shaik³

et al. 2011

The pyranocoumarin compound decursin and its isomer decursinol angelate (DA) are the major hydrophobic phytochemicals in the root of Angelica gigas Nakai (AGN, Korean Angelica), a major traditional medicinal herb. The ethanol extract of AGN and especially the purified decursin and DA have been shown to exhibit antitumor activities by our collaborative team and others. Although decursinol has been identified as a major hydrolysis metabolite of decursin and DA in vivo in previous pharmacokinetic studies with mouse and rat, other recently published results sharply disputed this conclusion. In this study, we set up a practical method for the concurrent analysis of decursin, DA, and decursinol in mouse plasma and tumor tissues by liquid-liquid extraction and HPLC-UV and applied the method to several animal experiments. Plasma or tumor homogenate was extracted directly with ethyl acetate. The extraction efficiency for decursin/DA (quantitated together) and decursinol was between 82-95 % in both mouse plasma and tumor homogenate. The lower limit of quantitation (LLOQ) was approximately 0.25 µg/mL for decursin/DA and 0.2 µg/mL for decursinol in mouse plasma. In a pilot pharmacokinetic study, male C57BL/6 mice were given a single dose of 4.8 mg decursin/DA mixture (~240 mg/kg) per mouse either by oral gavage or intraperitoneal injection. Maximum plasma concentrations for decursin/DA and decursinol were 11.2 and 79.7 µg/mL, respectively, when decursin/DA was administered via intraperitoneal injection, and 0.54 and 14.9 µg/mL via oral gavage. Decursin/DA and decursinol contents in the tumor tissues from nude mouse xenografts correlated very well with those in plasma. Overall, our results confirm the conclusion that the majority of decursin/DA hydrolyze to decursinol in rodent models with a tiny fraction remaining as the intact compounds administered.