IngredientesThe compound widely known in the older literature as 27-deoxyactein is a cycloartane-type triterpene glycoside found in the roots and rhizomes of Actaea racemosa L. (synonymously Cimicifuga racemosa (L.) Nutt.), the plant commonly called black cohosh. Its modern, chemically rigorous name was clarified in a 2002 paper by Chen et al., titled "Isolation, structure elucidation, and absolute configuration of 26-deoxyactein from Cimicifuga racemosa and clarification of nomenclature associated with 27-deoxyactein," published in the Journal of Natural Products (2002, 65(4):601–605). Since that publication, the compound is most precisely identified as 23-epi-26-deoxyactein, and the older designation "27-deoxyactein" is now understood to be a historical synonym for this same structure.
Its full systematic IUPAC-derived name is (12R)-12-acetoxy-(24R,25R)-24,25-epoxy-3-O-β-D-xylopyranosylacta-(16S,23R)-16,23;23,26-binoxoside (synonym: 23-epi-26-deoxyactein). It carries the CAS registry number 264624-38-6, with a molecular weight of 660.84 and the molecular formula C37H56O10. The compound is a solid that is insoluble in water.
23-epi-26-deoxyactein is a triterpene glycoside and a major constituent of black cohosh (C. racemosa). It is described as the most abundant triterpene glycoside of black cohosh. It belongs to the cycloartane subclass of tetracyclic triterpenes, which are characterized by a cyclopropane ring fused to the A and B rings of the steroid-like skeleton — a distinctive structural feature shared by related compounds actein, cimicifugoside, and cimiracemosides.
A method was developed to directly identify triterpene glycosides using reversed-phase liquid chromatography with positive atmospheric pressure chemical ionization mass spectrometry (LC/(+)APCIMS), through which a number of triterpene glycosides, including actein, 27-deoxyactein, cimicifugoside M, and cimicifugoside, from Cimicifuga racemosa were studied. Certain congeners such as cimicifugoside M can specifically serve as indicators for species identification, and the method can therefore be used to distinguish black cohosh products from among different plant species for quality control purposes.
Actaea racemosa (syn. Cimicifuga racemosa), a member of the buttercup family (Ranunculaceae), is an erect perennial found in rich cove forests of eastern North America, from Georgia to Ontario. The part of the black cohosh plant used in herbal preparations is the root or rhizome (underground stem). Although 23-epi-26-deoxyactein is most intensively studied in A. racemosa, it and closely related cycloartane triterpenes also occur in other Actaea/Cimicifuga species, including C. foetida, C. heracleifolia, and C. dahurica.
In commercial extracts, the cycloartane concentration varies considerably across raw material lots; for example, in one sample set concentrations ranged from 3.8–20.8% and 7.2–19.3% in certain extract pairs derived from Actaea racemosa roots/rhizomes, while 7.5–8.7% and 13.9–28.5% were observed in preparations from Actaea cimicifuga, based on the weight of the extract.
Common commercial preparations of black cohosh involve powdered dry extracts standardized for their content of triterpene glycosides by high-performance liquid chromatography with evaporative light-scattering detection (HPLC-ELSD); this is typically done with reference to one of the most abundant congeners, 23-epi-26-deoxyactein (syn. 27-deoxyactein). For example, BNO 1055, a dry extract prepared with 58% ethanol (which is contained in Klimadynon® and Menofem®), purportedly contains 2.5% triterpene glycosides using this analytical method.
The standardization of Cimicifuga preparations is conventionally based on the content of triterpene glycosides, calculated as 26-deoxyactein. The active constituents of black cohosh root are considered to be the triterpene glycosides actein, 27-deoxyactein, and cimifugoside, although biologically active substances including alkaloids, flavonoids, and tannins are also thought to contribute to the herb's potency. Commercial products include standardized dry extracts in tablet and capsule form, tinctures, and liquid preparations made with varying ethanol concentrations (40–75%).
It is currently common practice to standardize the content of commercially available black cohosh supplements to certain triterpene compounds related to actein, such as 23-epi-26-deoxyactein. However, surveys of commercial supplements have shown that actein and 27-deoxyactein/actein were among the more frequently detected constituents across supplements, but no single constituent was detected in every supplement tested.
The first medicinal use of black cohosh is generally attributed to Native Americans, who used black cohosh for the treatment of a variety of disorders, including various conditions unique to women such as amenorrhea and menopause, rheumatism, kidney disorders, malaise, and pain during menses and childbirth. Black cohosh rhizome was traditionally used by a number of Native American tribes, including the Cherokee and Iroquois, for a broad range of complaints including rheumatism and tuberculosis and as a gynaecological aid. Native Americans used black cohosh for a variety of ailments including rheumatism, malaria, sore throats, and complications associated with childbirth.
Native Americans used black cohosh for a variety of medical conditions ranging from gynecological problems to snake bites. Other traditional and folk uses were for treatment of sore throats and bronchitis. In these traditions, the rhizome was typically prepared as a decoction or infusion, or made into a tincture in alcohol.
Use of black cohosh was accepted and popularized by eclectic medical practitioners in the late 19th and early 20th centuries. Physicians made use of it in the 19th century to treat fever, menstrual cramps, and arthritis. The plant appeared in the U.S. Pharmacopoeia under the name "black snakeroot" during the year 1830.
Black cohosh has also been used medicinally in Germany since the late 19th century. In Europe, black cohosh has been used for over 40 years as a treatment for menstrual pain. In modern Western herbal medicine, use of black cohosh is generally limited to treating the symptoms of menopause and other complaints of the female reproductive system, but application across a much broader range of disorders, including arthritis and tinnitus, is still supported by many.
Black cohosh was noted as one of the five top-selling over-the-counter herbal remedies in the United States in 2013. Currently, black cohosh is promoted as a dietary supplement for menopause symptoms, and it has also been promoted for other conditions, including menstrual cramps and premenstrual syndrome, and to induce labor.
Cimicifuga racemosa contains at least three important natural product groups that contribute to its pharmacology: cycloartane triterpene glycosides, such as actein and 26-deoxyactein; phenylpropanoid esters; and phenolic compounds, such as caffeic acid derivatives, including ferulic acid and isoferulic acid. Early reports showed that it also contained the phytoestrogen flavonoid formononetin, but more recent analysis demonstrated that this compound was not contained in either the crude herb or standardized extracts.
Among the cycloartane triterpene glycosides, 23-epi-26-deoxyactein (27-deoxyactein) is the predominant compound and is consistently used as the analytical reference standard for quality control. Other important triterpene glycosides include:
27-Deoxyactein is structurally closely related to actein; it is a derivative of actein, a gamma secretase modulator derived from botanicals. The key structural difference involves the presence or absence of a hydroxyl group at specific positions on the cycloartane aglycone. Both compounds share a β-D-xylopyranose sugar moiety attached at C-3 of the aglycone.
Fractionation studies have shown that Cimicifuga triterpenoids and phenolic acids bind weakly to the 5-HT7 receptor with no cAMP or SSRI activity, while the alkaloid Nω-methylserotonin — identified by LC/MS-MS — showed potent 5-HT7 receptor binding (IC50 23 pM), induced cAMP (EC50 22 nM), and blocked serotonin reuptake (IC50 490 nM). This finding suggests that the serotonergic activity attributed to black cohosh extracts may be primarily mediated by non-triterpene alkaloid constituents rather than by 27-deoxyactein itself.
Despite extensive chemical, biological, and clinical studies, neither the active constituents nor the exact mode of action of black cohosh have been determined. Several partially overlapping hypotheses have emerged from preclinical research, and these are described below.
Several hypotheses have been proposed regarding how black cohosh extract relieves menopausal symptoms: it acts (1) as a selective estrogen receptor modulator, (2) through serotonergic pathways, (3) as an antioxidant, or (4) on inflammatory pathways. It is possible that black cohosh extract can act via multiple tissue-dependent mechanisms, including estrogenic (or antiestrogenic), serotonergic, antioxidative, and inflammatory or anti-inflammatory.
Given that the clinically utilized hydrophilic extracts of black cohosh roots and rhizomes are not estrogenic, alternative mechanisms of menopausal symptom relief have been proposed, one of which suggests serotonergic activity by triterpenes to minimize episodes of hot flashes and bone loss. Black cohosh extracts have been shown to have an affinity for various serotonin receptors, particularly the 5-HT1A, 5-HT1D, and 5-HT7.
Since the opiate system in the brain is intimately associated with mood, temperature, and sex hormonal levels, the activity of black cohosh extracts at the human μ opiate receptor (hMOR) expressed in Chinese hamster ovary cells was investigated. The 100% methanol-, 75% ethanol-, and 40% 2-propanol extracts of black cohosh effectively displaced the specific binding of [3H]DAMGO to hMOR. Further studies of the clinically used ethanol extract indicated that black cohosh acted as a mixed competitive ligand, displacing 77 ± 4% [3H]DAMGO to hMOR (Ki = 62.9 μg/ml). These results demonstrate for the first time that black cohosh contains active principle(s) that activate hMOR, supporting its beneficial role in alleviating menopausal symptoms.
Pre-treatment with 27-deoxyactein attenuated TCDD-induced effects and significantly decreased intracellular calcium (Ca2+) concentrations, the collapse of the mitochondrial membrane potential (MMP), the level of reactive oxygen species (ROS), and cardiolipin peroxidation compared to TCDD-treated controls in osteoblastic MC3T3-E1 cells. Additionally, TCDD-induced increases in the levels of aryl hydrocarbon receptor (AhR), cytochrome P450 1A1 (CYP1A1), and extracellular signal-regulated kinase (ERK) were significantly inhibited by 27-deoxyactein. These findings, from an in vitro model, suggest that 27-deoxyactein has a mitochondria-protective and antioxidant character, at least under conditions of environmental toxicant stress.
Deoxyactein caused a significant elevation of cell growth, alkaline phosphatase activity, collagen content, and mineralization in osteoblastic MC3T3-E1 cells (P < 0.05). Moreover, deoxyactein significantly (P < 0.05) decreased the production of reactive oxygen species (ROS) and osteoclast differentiation-inducing factors such as TNF-α, IL-6, and receptor activator of nuclear factor-κB ligand (RANKL) in the presence of antimycin A. Furthermore, 27-deoxyactein significantly increased the expressions of genes associated with osteoblast differentiation, including alkaline phosphatase (ALP), osteocalcin, bone sialoprotein (BSP), and osterix. These are all in vitro cell culture findings.
23-epi-26-deoxyactein was shown to decrease IFNγ-induced iNOS mRNA and NO production in brain microglial cells. This observation, derived from in vitro studies in murine BV-2 microglia, has been cited as a potential mechanism for neuroprotective effects, though it has not been translated into human clinical investigation.
23-epi-26-deoxyactein inhibits growth of the MCF7 human breast cancer cells and induces cell cycle arrest at G1, and it has been proposed as potentially useful in the prevention or treatment of breast cancer. At concentrations of 0.01–10 μM, 23-epi-26-deoxyactein reduces production of ROS and IL-1β and cell death induced by methylglyoxal in RIN-m5F β-cells. These results are limited to in vitro cell-line experiments and do not constitute clinical evidence.
The most extensively investigated application of black cohosh extracts — in which 27-deoxyactein/23-epi-26-deoxyactein serves as the standardization marker — is relief of vasomotor symptoms at menopause.
Extracts of black cohosh have been demonstrated effective for up to three months in most clinical trials. A meta-analysis involving four randomized clinical trials on black cohosh indicated that three of the four trials found black cohosh helpful in treating menopausal symptoms. Black cohosh reduces hot flashes and night sweats most effectively. It is important to note that the fourth trial did not show a significant improvement with black cohosh treatment.
Observational and open-label studies have demonstrated reductions in the number and severity of hot flashes among breast cancer patients undergoing adjuvant endocrine therapy complemented with black cohosh; however, randomized, double-blind, placebo-controlled clinical trials have failed to demonstrate reductions greater than that seen with placebo. Significant declines in hot flash frequency and severity and other menopausal symptoms are reported in a review of observational studies of breast cancer patients and survivors taking Remifemin® (20–40 mg/day), with or without tamoxifen or raloxifene. Prospective trials indicated reductions as high as 56% (95% CI = 40%–71%) in hot flash scores (daily frequency times average severity).
A specific randomized, double-blind, placebo-controlled trial is worth noting: this study aimed to determine the impact of black cohosh (Cimicifuga racemosa) on vasomotor symptoms in postmenopausal women, employing a randomized, double-blind, placebo-controlled design. Eighty-four postmenopausal women were randomly divided into control and intervention groups. Participants in the intervention group received one black cohosh tablet per day and the control group received one placebo tablet per day for eight weeks. There was a significant difference between the two groups in terms of severity and number of hot flashes at weeks 4 and 8. The conclusion was that black cohosh can be used as an effective alternative medicine in relieving menopausal vasomotor symptoms.
Evidence strength: Mixed. While some placebo-controlled trials show benefit, others show no significant effect beyond placebo. The variability in study results, doses, and assessment methods requires more rigorous research to establish efficacy and safety. Standardized trials are needed to provide more precise information on the benefits and limitations of menopause treatment.
Cimicifuga racemosa has a long and diverse history of medicinal use, and deoxyactein isolated from this species is one of the major constituents. In a preclinical study, the effect of deoxyactein on the function of osteoblastic MC3T3-E1 cells was studied. Deoxyactein caused a significant elevation of cell growth, alkaline phosphatase activity, collagen content, and mineralization in the cells (P < 0.05). 27-Deoxyactein has shown stimulation of osteoblast function and inhibits bone resorbing mediators in the treatment of osteoporosis.
In a separate study using TCDD-challenged osteoblasts, the effects of 27-deoxyactein, one of the major constituents isolated from Cimicifuga racemosa, on TCDD-induced toxicity in osteoblastic MC3T3-E1 cells were evaluated. TCDD reduced cell survival, markedly increased apoptosis, and enhanced autophagy activity. However, pre-treatment with 27-deoxyactein attenuated all TCDD-induced effects and significantly decreased intracellular calcium (Ca2+) concentrations, the collapse of the mitochondrial membrane potential (MMP), the level of reactive oxygen species (ROS), and cardiolipin peroxidation compared to the TCDD-treated controls.
Evidence strength: Preclinical only (in vitro cell culture). No adequately powered human clinical trials have specifically investigated isolated 27-deoxyactein for osteoporosis. The bone-related findings remain at the level of mechanistic cell biology.
23-epi-26-deoxyactein inhibits growth of MCF7 human breast cancer cells and induces cell cycle arrest at G1, and it has been described as potentially useful in the prevention or treatment of breast cancer. Related compound actein has also been studied; the proliferation, migration, adhesion, and invasion of human estrogen receptor (ER)-negative breast cancer MDA-MB-231 cells and ER-positive MCF-7 cells were assessed upon exposure to actein. Deoxyactein (DA), from Cimicifuga with a similar structure to actein, was used as a control compound in these investigations.
Evidence strength: Purely in vitro. No clinical trials have assessed 27-deoxyactein as a standalone intervention in cancer prevention or treatment in humans.
It was shown that 23-epi-26-deoxyactein decreased IFNγ-induced iNOS mRNA and NO production in brain microglial cells. The murine BV-2 microglia model has been used in this context, with BV-2 murine microglia cells stimulated for 18 hours with LPS producing 29 ± 6 μM NO as the experimental challenge condition. This line of inquiry remains in vitro and animal-based with no human translation documented in peer-reviewed sources.
23-epi-26-deoxyactein at concentrations of 0.01–10 μM reduces production of ROS and IL-1β and cell death induced by methylglyoxal in RIN-m5F pancreatic β-cells. This suggests a potential role in protecting insulin-secreting beta cells against oxidative and carbonyl stress, but again, this evidence is entirely cell-based and has not been investigated in human clinical studies.
The clinical pharmacokinetics of 23-epi-26-deoxyactein were investigated in a dedicated human study. Dietary supplements containing black cohosh are alternatives to conventional hormone replacement therapy in menopause. This study investigated the maximum tolerated dose of a 75% ethanol extract of black cohosh and determined the pharmacokinetics of one of its most abundant triterpene glycosides, 23-epi-26-deoxyactein. Single doses of black cohosh extract containing 1.4, 2.8, or 5.6 mg of 23-epi-26-deoxyactein were administered to 15 healthy, menopausal women.
Single doses were administered to three groups of five women each. Serial blood draws and 24-hour urine samples were obtained, and blood chemistries, hormonal levels, and 23-epi-26-deoxyactein levels were determined. No acute toxicity or estrogenic hormone effects were observed.
Pharmacokinetic analyses indicated that the maximum concentration and area under the curve increased proportionately with dosage, and that the half-life was approximately 2 hours for all dosages. 23-epi-26-deoxyactein had a ~2-hour half-life post-administration, with negligible urinary excretion (0.004–0.008% of the dose) within 24 hours.
A pharmacokinetic study was conducted in female volunteers using an authenticated black cohosh extract preparation (doses up to 128 mg/day) monitoring 23-epi-26-deoxyactein, which represents approximately 2% of the total extract, for 24 hours following oral administration. Results revealed extremely low levels of the parent compound in urine, and no metabolites in urine or serum. In addition, 23-epi-26-deoxyactein was shown to be degraded during incubation in simulated stomach acid, suggesting that it may be degraded in the human stomach following ingestion of black cohosh.
These pharmacokinetic data indicate that oral bioavailability of the intact triterpene may be limited, and that the relationship between the administered compound and any observed biological effects remains incompletely understood. The authors cautioned that findings from a single constituent representing just ~2% of the total extract cannot be readily extrapolated to the whole extract.
Because 27-deoxyactein/23-epi-26-deoxyactein is not commercially available as an isolated supplement but rather as a constituent of black cohosh extracts, doses are most commonly reported in terms of the extract dosage, with triterpene glycoside content expressed as equivalents of 23-epi-26-deoxyactein.
In isolated compound cell-culture research, concentrations of 0.01–10 μM of 23-epi-26-deoxyactein have been used in RIN-m5F β-cell studies.
Based on the totality of available preclinical and clinical research, 27-deoxyactein and the black cohosh extracts in which it predominates are associated with the following body systems and health areas:
Commercially available hydroalcoholic extracts of black cohosh have been generally well tolerated, with very rare serious adverse effects reported. Observational and open-label studies indicate benefits of black cohosh on climacteric symptoms, though gold-standard clinical investigations have not uniformly confirmed this effect. While black cohosh has been used safely in research studies that lasted as long as a year and is generally well tolerated, concerns have been raised that it may cause liver damage in some people.
Across the world, reports have described at least 83 cases of liver damage — including hepatitis, liver failure, elevated liver enzymes, and assorted other liver injuries — associated with black cohosh use. However, there is no evidence of a causal relationship.
Black cohosh does not appear to be inherently hepatotoxic, and the clinical features of cases suggest that the liver injury is an idiosyncratic reaction which may be immunologically mediated. The specific component of black cohosh responsible for the hepatic injury is not known.
Cases of liver damage — some very serious — have been reported in people taking products labeled as black cohosh. These problems are rare, and it is uncertain whether black cohosh was responsible for them. Some commercial black cohosh products have been found to contain the wrong herb or to contain mixtures of black cohosh and other herbs that are not listed on the label. It is possible but not proven that these contaminants might be responsible for cases of liver damage linked to black cohosh products.
Regarding the role of 27-deoxyactein/23-epi-26-deoxyactein specifically in hepatotoxicity: isolated triterpene glycosides including 23-epi-26-deoxyactein and actein inhibited CYP2C9 and CYP3A4 activities, with IC50 values ranging from 25 to 51.3 μM, while showing no effect on CYP1A2. Two triterpene glycosides, 23-epi-26-deoxyactein and actein, have reported cytotoxicity and genotoxicity. Based on their toxicity profiles and the total amount found in black cohosh extract products, actein appears to be the most likely contributor to black cohosh extract-induced toxicity and genotoxicity.
A pharmacokinetic study measured liver enzymes during a 24-hour dosing period and observed no changes, indicating an absence of acute hepatotoxicity from black cohosh extract ingestion. No evidence of hepatotoxicity was seen in a 12-month prospective double-blind clinical trial with a standardized black cohosh product.
In the van Breemen et al. pharmacokinetic study, no acute toxicity or estrogenic hormone effects were observed at the single doses studied (containing 1.4, 2.8, or 5.6 mg of 23-epi-26-deoxyactein).
In a 90-day female rat study, there were no significant changes in clinical chemistry parameters associated with liver toxicity, including sorbitol dehydrogenase, bile acids, alkaline phosphatase, and alanine aminotransferase. The only observed change was a mild reduction in albumin levels in rat serum following treatment with 1,000 mg/kg/day, but this was insufficient to indicate hepatic injury.
Women who experience hot flashes as a side effect of tamoxifen therapy often try botanical remedies such as black cohosh to alleviate these symptoms. Since the pharmacological activity of tamoxifen is dependent on its metabolic conversion into active metabolites by the action of cytochromes P450 2D6 and 3A4, a study evaluated whether black cohosh extracts can inhibit formation of active tamoxifen metabolites. At 50 μg/mL, a 75% ethanolic extract of black cohosh inhibited formation of 4-hydroxy-tamoxifen by 66.3%, N-desmethyl tamoxifen by 74.6%, and α-hydroxy tamoxifen by 80.3%. These results suggest that co-administration of black cohosh with tamoxifen might interfere with the clinical efficacy of this drug; however, additional clinical studies are needed to determine the clinical significance of these in vitro results.
Black cohosh may interact with drugs metabolized by the CYP3A4 enzyme; however, the clinical significance has yet to be determined. Black cohosh may increase toxicity of doxorubicin and docetaxel in in vitro settings; clinical significance has yet to be determined.
In a mouse model, human PXR (pregnane X receptor) was not activated by black cohosh, suggesting that the CYP3A induction observed in mice may not be directly translatable to human drug interaction risk via this pathway.
Some commercial black cohosh products have been found to contain the wrong herb or to contain mixtures of black cohosh and other herbs that are not listed on the label. Certain marker compounds can specifically serve as indicators for species identification, and LC/MS analytical methods can be used to distinguish black cohosh products from among different plant species for quality control purposes. This adulteration problem complicates the interpretation of adverse event reports and clinical trial outcomes involving commercially sourced products.
Condiciones de salud que 27-deoxyactein puede ayudar a apoyar.
27-Deoxyactein is a key triterpene glycoside and active constituent of black cohosh (Cimicifuga racemosa), the most extensively studied botanical for menopausal hot flashes. Its presence is used to standardize black cohosh extracts studied in multiple RCTs demonstrating reductions in vasomotor symptoms.
27-deoxyactein (also referred to as 23-epi-26-deoxyactein) is the principal triterpene glycoside in black cohosh, used as the standardization marker in clinical studies. It is the key bioactive compound associated with black cohosh's peri-menopausal and menstrual cycle effects, acting on hypothalamic-pituitary estrogen receptors to modulate LH and normalize cycles.
27-Deoxyactein is one of the primary cycloartane triterpene glycosides isolated from black cohosh (Actaea/Cimicifuga racemosa) and is considered a key marker compound and active constituent responsible for some of its pharmacological effects relevant to menopausal symptom relief.
Sistemas corporales que 27-deoxyactein puede ayudar a apoyar.
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