Atractylenolide Iii

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 220(SRC), determined from a structure estimation method(2), indicates that atractylenolide III is expected to have moderate mobility in soil(SRC). Volatilization of atractylenolide III from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.5X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Atractylenolide III is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.4X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Biodegradation data in soil were not available(SRC, 2013).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 220(SRC), determined from a structure estimation method(2), indicates that atractylenolide III is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 9.5X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 150(SRC), from an estimated log Kow of 3.81(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC). Atractylenolide III is expected to undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(3). Biodegradation data in water were not available(SRC, 2013).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), atractylenolide III, which has an estimated vapor pressure of 8.4X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase atractylenolide III is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3.7 hours(SRC), calculated from its rate constant of 1.0X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase atractylenolide III may be removed from the air by wet or dry deposition(SRC). Atractylenolide III contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Atractylenolide III is extracted from the Chinese medicinal plant Atractylodes macrocephala(1), Chinese Bai-Zhu(2). The sesquiterpenoids present in A. ovata rhizome were identified as atractylenolide III and atractylon, by spectroscopic analysis(3).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of atractylenolide III can be estimated to be 220(SRC). According to a classification scheme(2), this estimated Koc value suggests that atractylenolide III is expected to have moderate mobility in soil.

/ALTERNATIVE and IN VITRO TESTS/ The rhizome of Atractylodes ovata (Bai Zhu in Chinese) is a widely used traditional Chinese herb in Taiwan as a tonic agent. In this paper, four sesquiterpenoids, namely atractylon, and atractylenolides I, II, and III, were isolated from the n-hexane extract of A. ovata and were evaluated for cytotoxic effects in vitro. Atractylon significantly inhibited the growth of human leukemia cell line HL-60 and mouse leukemia cell line P-388, and showed low cytotoxicity against primary cultures of normal human peripheral blood mononuclear cells at 15 ug/mL for 12 hr. Atractylon had a dose-dependent antiproliferative effect on the two tumor cell lines. In accordance with DNA fragment increases and PARP protein decreases, atractylon at 15 ug/mL for 6 hr induced apoptosis in HL-60 cells. Moreover, atractylon inhibited the viability of P-388 cells and induced apoptosis after 15 microg/ml treatment for 12 hr in an in vitro assay. However, atractylenolide I at 30 ug/mL for 12 hr also induced apoptosis in HL-60 and P-388 cells, but atractylenolides II and III showed no significant inhibition effects on tumor cell growth. As the above results suggested, atractylon and atractylenolide I were the major cytotoxic principle constituents of A. ovata on leukemia cell lines.

/ALTERNATIVE and IN VITRO TESTS/ The dried rhizome of Bai Zhu (Atractylodes ovata) is widely used as a Chinese herbal medicine. Two sesquiterpenolides of similar structures (atractylenolide I, AT-I; atractylenolide III, AT-III) were isolated from dried rhizome of Atractylodes ovata. Incubation of AT-I with recombinant human Cu,Zn-superoxide dismutase (rhCu,Zn-SOD) resulted in rhCu,Zn-SOD fragmentations and Zn releases. However, these were not observed in the AT-III reaction. The AT-1 showed dose-dependent cytotoxic activities (7.5, 15, and 30 ug/mL) on the human promyeloleukemic HL-60 cells while AT-III did not, and the IC50 of the former being 10.6 ug/mL (corresponding to 46 uM) on 12 hr-treated cells...

An estimated BCF of 150 was calculated in fish for atractylenolide III(SRC), using an estimated log Kow of 3.81(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC).

The Henry's Law constant for atractylenolide III is estimated as 9.5X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that atractylenolide III is expected to be essentially nonvolatile from moist soil and water surfaces(2). Atractylenolide III is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.4X10-8 mm Hg(SRC), determined from a fragment constant method(3).

/ALTERNATIVE and IN VITRO TESTS/ Molecules that enhance chondrogenic differentiation in mesenchymal stem cells (MSCs) were identified and isolated using an in vitro Gli reporter gene assay in MSCs incorporating a Sonic Hedgehog (Shh) target. Atractylenolide III, which promoted Gli1-mediated transcriptional activity, was isolated from an ethyl acetate extract of the Rhizoma, Atractylodis macrocephalae. After dehydration, atractylenolide III was transformed to atractylenolide I. Both atractylenolides were confirmed by MS, UV, IR, (1)H- and (13)C-NMR spectra. Atractylenolide III (which contains -OH at the 8-position) and atractylenolide I (which lacks -OH at the 8-position) were found to effectively promote the activity of the Gli promoter. While the hydroxyl group of atractylenolide III was not essential for the effect of atractylenolide, its effect was dependent on Shh signaling. Phenotypic cellular analysis indicated that atractylenolides induced MSCs to differentiate into chondrocytes, as shown by increased expression of specific chondrogenic markers including collagen II, aggrecan and the cartilage related transcription factor, Sox9. Atractylenolides significantly increased the expression of Shh and its target gene Gli-1, indicating that Shh signaling was activated by atractylenolides. Moreover, inhibition of Shh signaling reduced the effect of atractylenolides on the chondrogenic phenotype. The discovery that atractylenolides induce chondrocytes from MSCs is promising for bony disease therapy.

/ALTERNATIVE and IN VITRO TESTS/ The rhizome of Atractylodes ovata (Bai Zhu in Chinese) is a widely used traditional Chinese herb in Taiwan as a tonic agent. In this paper, four sesquiterpenoids, namely atractylon, and atractylenolides I, II, and III, were isolated from the n-hexane extract of A. ovata and were evaluated for cytotoxic effects in vitro. Atractylon significantly inhibited the growth of human leukemia cell line HL-60 and mouse leukemia cell line P-388, and showed low cytotoxicity against primary cultures of normal human peripheral blood mononuclear cells at 15 ug/mL for 12 hr. Atractylon had a dose-dependent antiproliferative effect on the two tumor cell lines. In accordance with DNA fragment increases and PARP protein decreases, atractylon at 15 ug/mL for 6 hr induced apoptosis in HL-60 cells. Moreover, atractylon inhibited the viability of P-388 cells and induced apoptosis after 15 microg/ml treatment for 12 hr in an in vitro assay. However, atractylenolide I at 30 ug/mL for 12 hr also induced apoptosis in HL-60 and P-388 cells, but atractylenolides II and III showed no significant inhibition effects on tumor cell growth. As the above results suggested, atractylon and atractylenolide I were the major cytotoxic principle constituents of A. ovata on leukemia cell lines.

/ALTERNATIVE and IN VITRO TESTS/ The rhizome of Atractylodes ovata De Candolle is popularly used in traditional Chinese medicine to treat gastrointestinal diseases. However, the major gastroprotective compounds of A. ovata have not been identified. This study reports on the principal gastro- protective component of A. ovata. Five sesquiterpenoids (atractylon, atractylenolides I, II, III and biatractylolide) were isolated from the extracts of A. ovata rhizome via silica gel column chromatography. The gastroprotective effects of these five sesquiterpenoids were measured in in-vitro ethanol-induced primary culture rat gastric mucosal (PRGM) cell damage and in-vivo ethanol-induced acute rat gastric ulcer models. Atractylon, atractylenolide I and biatractylolide were strongly toxic in PRGM cells, whilst atractylenolides II and III were not. Atractylenolide II did not show cytoprotective effects, but oral administration of atractylenolide III dose-dependently prevented ethanol-induced PRGM cell death and cell membrane damage. The EC50 values were 0.27 and 0.34 mM, respectively. In the in-vivo assay, atractylenolide III 10 mg/kg significantly reduced 70% ethanol-induced Wistar rat gastric ulcer. Atractylenolide III could inhibit matrix metalloproteinase (MMP)-2 and MMP-9 expression through upregulation of tissue inhibitors of metalloproteinase from the gastric ulcerated tissues. Atractylenolide III was the major gastroprotective component of A. ovata in ethanol-induced acute gastric ulcer. It is suggested that the gastroprotective mechanism of atractylenolide III was via inhibition of the MMP-2 and MMP-9 pathway.

The rate constant for the vapor-phase reaction of atractylenolide III with photochemically-produced hydroxyl radicals has been estimated as 1.0X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3.7 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Atractylenolide III is expected to undergo hydrolysis in the environment due to the presence of functional groups that hydrolyze under environmental conditions(2). Atractylenolide III contains chromophores that absorb at wavelengths >290 nm(2) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Occupational exposure to atractylenolide III may occur through inhalation and dermal contact with this compound at workplaces where atractylenolide III is extracted or used. Use data indicate that the general population may be exposed to atractylenolide III via ingestion as a medication. (SRC)