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WO2025036933A1 - Moyens et procédés pour réduire l'effet oestrogénique d'un xénoestrogène - Google Patents

Moyens et procédés pour réduire l'effet oestrogénique d'un xénoestrogène Download PDF

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Publication number
WO2025036933A1
WO2025036933A1 PCT/EP2024/072897 EP2024072897W WO2025036933A1 WO 2025036933 A1 WO2025036933 A1 WO 2025036933A1 EP 2024072897 W EP2024072897 W EP 2024072897W WO 2025036933 A1 WO2025036933 A1 WO 2025036933A1
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WIPO (PCT)
Prior art keywords
composition
xenoestrogen
compound
isoflavone
formula
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English (en)
Inventor
Dino GRGIC
Doris Marko
Barbara Katharina NOVAK
Elisabeth VARGA
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DSM IP Assets BV
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DSM IP Assets BV
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12F—RECOVERY OF BY-PRODUCTS OF FERMENTED SOLUTIONS; DENATURED ALCOHOL; PREPARATION THEREOF
    • C12F3/00—Recovery of by-products
    • C12F3/10—Recovery of by-products from distillery slops
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
    • A23K10/37—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms from waste material
    • A23K10/38—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms from waste material from distillers' or brewers' waste
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/111—Aromatic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens

Definitions

  • the present invention relates to a composition, a method for reducing estrogenic effect(s), use of a compound and a composition for use in treatment, amelioration and/or prevention.
  • Xenoestrogens are compounds capable of eliciting a hormonal, in particular an estrogenic response in an animal body, which is different from their place of origin or synthesis.
  • Xenoestrogens may be of synthetic origin, or stem from natural organisms such as plants or fungi.
  • an effect on the endocrine system may be desired, e.g. in xenoestrogen- effected contraception.
  • estrogenic effects are associated with increased cancer risk, reduced fertility in males and females, environmental damages etc.
  • Zearalenone and structurally and functionally similar derivatives thereof are produced by various Fusarium species, and belong to the group of fungal xenoestrogens, also referred to as mycoestrogens.
  • mycoestrogens are known to cause serious damages in the agriculture industry in terms of both, animal health as well as economically.
  • zearalenone has been described to negatively affect male and female animals, causing damage to liver, hematotoxic effects, and, most prominently, disorders associated with estrogenic effect such as infertility, vulva swelling, uterus enlargement, pseudopregnancy, stillbirths, ovary cysts, enlarged mammary glands, feminization of testicular atrophy, reduced sperm concentration etc. (Ropejko et al. 2021. Toxins 13(1): 25).
  • Phytoestrogens are produced by plants, and comprise various compounds of the groups of coumestans, prenylflavonoids, lignans, stilbenes and isoflavones. Numerous studies have shown adverse effects of phytoestrogens on animals' reproduction organs and functions, e.g. Rochester et al. 2009. Comp Biochem Physiol A Mol Integr Physiol 154(3):279; Grgic et al. 2021 . Toxins 13(12):836, associated with the estrogenic effect of these compounds.
  • isoflavones have also gained attention for beneficial health effects, for instance in individuals suffering from obesity, metabolic syndrome, type 2 diabetes, osteoporosis, and/or irritable bowel syndrome, for providing protection against reactive oxygen species, and potentially supporting neuronal health and cognitive performance (e.g. Rietjens et al. 2016. Br J Pharmacol 174(11):1263).
  • composition e.g. a nutritional composition
  • a composition comprising at least one isoflavone, and at least a second compound having formula (I):
  • R is selected from H and COOH.
  • Such a composition allows providing the desirable non-estrogenic effects of the at least one isoflavone, but has a reduced estrogenic potential.
  • such a composition elicits reduced estrogenic effect or even no estrogenic effects at all, e.g. upon consumption.
  • the composition further comprises one or more further compounds selected from: One or more chemical(s) capable of modifying mycotoxin(s); one or more polypeptide(s) capable of modifying mycotoxin(s); one or more organic absorbent(s); one or more inorganic absorbent(s); one or more live, inactivated, lyophilized and/or dormant microorganism(s) capable of modifying mycotoxin(s); one or more plant product(s); one or more flavoring compound(s); and one or more vitamin(s).
  • said modifying mycotoxin(s) is a detoxification of said mycotoxin(s); or a reduction in toxicity of said mycotoxin(s).
  • said one or more chemicals capable of modifying mycotoxin(s) is/are one or more metabisulfite salt(s), such as sodium metabisulfite.
  • said one or more polypeptide(s) capable of modifying mycotoxin(s) is/are one or more peptidase(s), hydrolase(s), esterase(s), lactonase(s), epoxidase(s), peroxidase(s), and/or peroxygenase(s).
  • said one or more further polypeptide(s) capable of modifying one or more mycotoxin(s) is/are e.g. fumonisin esterase (e.g. as disclosed in WO 2016/134387 A1), ochratoxin peptidase (e.g.
  • zearalenone lactonase e.g. as disclosed in WO 2020/025580 A1 , or in WO 2022/073649 A1
  • ergopeptine hydrolase e.g. as disclosed in WO 2014/056006 A1
  • said one or more organic absorbent(s) is/are live, inactivated, lyophilized, dormant, and/or dead whole-yeast or yeast-derived product such as e.g. yeast cell wall, or yeast oligosaccharides such as e.g. mannan.
  • said one or more inorganic absorbent(s) is/are diatomaceous earth and/or clay mineral such as e.g. kaolins or kaolinites, smectites such as e.g. montmorillonites, illites or chlorites; in particular bentonite.
  • clay mineral such as e.g. kaolins or kaolinites, smectites such as e.g. montmorillonites, illites or chlorites; in particular bentonite.
  • said one or more live, inactivated, lyophilized and/or dormant microorganism(s) capable of modifying mycotoxin(s) is/are selected from the group consisting of Trichosporon and Apiotrichum genera (e.g. as disclosed in WO 03/053161 A1) and the Coriobacteriaceae family (e.g. as disclosed in EP 3 501 526 A1).
  • said one or more plant product(s) is/are e.g., seaweed, preferably seaweed meal; and/or algae, preferably algae meal; and/or thistle, preferably thistle seeds; and/or glycyrrhiza plant preparation, preferably glycyrrhiza meal and/or glycyrrhiza extract, e.g. as disclosed in WO 2018/121881 A1.
  • said one or more flavoring compound(s) is/are e.g., plant extract e.g. from oregano, thyme, Wintergreen, caraway, marjoram, mint, peppermint, anise, orange, lemon, fennel, star anise, clove, cinnamon and/or garlic; and/or essential oil such as e.g.
  • said one or more vitamin(s) is/are e.g. vitamin A, D, E, K, C, B1 , B2, B3, B4, B5, B6, B7, B8, B9 and/or B12.
  • the at least one isoflavone is selected from genistein (CAS no. 446-72-0), daidzein (CAS no. 486-66-8), glycitein (CAS no. 40957-83-3) and equol (CAS no. 531-95-3).
  • the composition is foodstuff; fodder; feed; silage; wet distillers grain; dried distillers grain with solubles; intermediate/s thereof; and/or mixture/s thereof; and/or (ii) the composition comprises cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • the invention relates to a method for reducing estrogenic effect(s) of a xenoestrogen, comprising forming a mixture of the xenoestrogen with a compound having formula (I):
  • R is selected from H and COOH.
  • said step of forming a mixture of the xenoestrogen with the compound comprises contacting the xenoestrogen with the compound.
  • the invention relates to a method for reducing estrogenic effect(s) of a composition (e.g. a nutritional composition) comprising a xenoestrogen, comprising forming a mixture of the composition comprising the xenoestrogen with said compound.
  • a composition e.g. a nutritional composition
  • said step of forming a mixture of the composition with the compound comprises contacting the composition with the compound.
  • Estrogenic effect(s) may be determined e.g. by using the human endometrial adenocarcinoma cell line “Ishikawa” as described e.g. by Grgic et al. 2022. Arch Toxicol. 96(12): 3385-3402.
  • the invention relates to a method for reducing estrogenic effect(s) of a xenoestrogen on an animal cell, comprising the step of contacting the animal cell with a compound having formula (I):
  • R is selected from H and COOH.
  • said animal cell (human or non-human animal cell) is an animal cell comprising one or more estrogen receptor(s), preferably one or more of the estrogen receptor isoform(s) alpha and beta.
  • said compound having formula (I) is provided to the animal cell prior to a contact with the xenoestrogen. In some embodiments, said compound having formula (I) is provided to the animal cell at the same time as the xenoestrogen. In some embodiments, said compound having formula (I) is provided to the animal cell after a previous contact of the xenoestrogen with the animal cell.
  • the invention relates to a method for manufacturing a composition (e.g. for manufacturing a nutritional composition), the method comprising the steps of providing a compound having formula (I):
  • R is selected from H and COOH
  • a composition will be produced which is less prone to causing estrogenic effect(s).
  • a such produced composition has a reduced estrogenic potential.
  • a method for manufacturing a composition is a method for increasing the safety of said composition.
  • the composition is foodstuff; fodder; feed; silage; wet distillers grain; dried distillers grain with solubles; intermediate/s thereof; and/or mixture/s thereof; and/or (ii) the composition comprises cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • the composition of the method for manufacturing a composition comprises a xenoestrogen.
  • the xenoestrogen is a phytoestrogen, preferably an isoflavone, more preferably an isoflavone selected from genistein, daidzein, glycitein and equol.
  • the invention relates to a use of a compound having formula (I):
  • R is selected from H and COOH; for reducing estrogenic effect(s) of a xenoestrogen.
  • the xenoestrogen is a phytoestrogen, preferably an isoflavone, more preferably an isoflavone selected from genistein, daidzein, glycitein and equol.
  • the invention relates to a composition (e.g. nutritional composition) for use in treatment, amelioration and/or prevention of symptoms associated with estrogenic effect(s) of a xenoestrogen; wherein the composition comprises at least a compound having formula (I):
  • R is selected from H and COOH.
  • the composition for use in treatment, amelioration and/or prevention of symptoms associated with estrogenic effect(s) of a xenoestrogen
  • (i) is foodstuff; fodder; feed; silage; wet distillers grain; dried distillers grain with solubles; intermediate/s thereof; and/or mixture/s thereof; and/or (ii) comprises cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • the xenoestrogen is a phytoestrogen, preferably an isoflavone, more preferably an isoflavone selected from genistein, daidzein, glycitein and equol.
  • the compound having formula (I) is (E)-2,4-dihydroxy-6-(10- hydroxy-6-oxo-1-undecen-1-yl)benzoic acid or (E)-1-(3,5-dihydroxy-phenyl)-10-hydroxy-1- undecen-6-one, as described e.g. by Vekiru et al. 2016. World Mycotoxin Journal 9(3): 353-363.
  • the compound is a mixture of both, (E)-2,4-dihydroxy-6-(10-hydroxy-6- oxo-1 -undecen-1-yl)benzoic acid and (E)-1-(3,5-dihydroxy-phenyl)-10-hydroxy-1-undecen-6- one.
  • the compound is provided by modifying (3S,11E)-14,16-dihydroxy- 3-methyl-3,4,5,6,9,10-hexahydro-1 H-2-benzoxacyclotetradecin-1 ,7(8H)-dione to (E)-2,4- dihydroxy-6-(10-hydroxy-6-oxo-1-undecen-1-yl)benzoic acid and/or (E)-1-(3,5-dihydroxy- phenyl)-10-hydroxy-1-undecen-6-one; e.g.
  • the invention is further characterized by the following items:
  • Composition e.g. nutritional composition
  • Composition comprising at least a first compound, wherein the at least first compound is at least one isoflavone; and at least a second compound having formula (I):
  • Composition e.g. nutritional composition
  • Composition comprising at least a first compound, wherein the at least first compound is at least one isoflavone; and at least a second compound having formula (I):
  • composition e.g. nutritional composition
  • comprising at least one isoflavone comprising at least one isoflavone
  • Item 4 The composition according to item 3, wherein the means for converting (3S, 11 E)- 14,16-dihydroxy-3-methyl-3,4,5,6,9, 10-hexahydro-1 H-2-benzoxacyclotetradecin-1 ,7(8H)-dione is/are an enzyme, preferably a lactonase.
  • Item 5 The composition according to any one of the preceding items, wherein the at least second compound is/are (E)-2,4-dihydroxy-6-(10-hydroxy-6-oxo-1-undecen-1-yl)benzoic acid and/or (E)-1-(3,5-dihydroxy-phenyl)-10-hydroxy-1-undecen-6-one.
  • Item 6 The composition according to any one of the preceding items, wherein the composition further comprises one or more further compounds selected from: one or more chemicals capable of modifying mycotoxin(s); one or more polypeptides capable of modifying mycotoxin(s); one or more organic absorbent(s); one or more inorganic absorbents; one or more live, inactivated, lyophilized and/or dormant microorganisms capable of modifying mycotoxin(s); one or more plant products; one or more flavoring compounds; and one or more vitamins.
  • Item 7 The composition according to any one of the preceding items, wherein the at least one isoflavone is selected from genistein, daidzein, glycitein and equol.
  • Item 8 The composition according to any one of the preceding items, wherein
  • composition is foodstuff; fodder; feed; silage; wet distillers grain; dried distillers grain with solubles; intermediate/s thereof; and/or mixture/s thereof; and/or wherein
  • the composition comprises cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • Item 9 Method for reducing estrogenic effect(s) and/or endocrine impact(s) of a xenoestrogen, comprising forming a mixture of the xenoestrogen with a compound having formula (I):
  • Item 10 The method according to item 9, wherein said forming a mixture comprises the step of contacting the xenoestrogen with the compound.
  • Item 11 Method for reducing estrogenic effect(s) and/or endocrine impact(s) of a xenoestrogen on an animal cell, comprising the step of contacting the animal cell with a compound having formula (I): (I), preferably wherein R is selected from H and COOH.
  • Item 12 Method for manufacturing a composition (e.g. a nutritional composition), the method comprising the steps of
  • Item 14 The method according to any one of items 12-13, wherein
  • composition is foodstuff; fodder; feed; silage; wet distillers grain; dried distillers grain with solubles; intermediate/s thereof; and/or mixture/s thereof; and/or wherein
  • the composition comprises cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • Item 15 The method according to any one of items 12-14, wherein the composition comprises a xenoestrogen.
  • Item 16 The method according to any one of items 12-15, wherein the composition comprises a phytoestrogen, preferably an isoflavone, more preferably an isoflavone selected from genistein, daidzein, glycitein and equol.
  • a phytoestrogen preferably an isoflavone, more preferably an isoflavone selected from genistein, daidzein, glycitein and equol.
  • Item 17 The method according to any one of items 9-16, wherein the compound is provided by providing (3S,11 E)-14,16-dihydroxy-3-methyl-3,4,5,6,9,10-hexahydro-1 H-2- benzoxacyclotetradecin-1 ,7(8H)-dione; and means for converting (3S,11 E)-14,16-dihydroxy-3- methyl-3,4,5,6,9,10-hexahydro-1 H-2-benzoxacyclotetradecin-1 ,7(8H)-dione to a compound having formula (I).
  • Item 18 The method according to item 17, wherein the means for converting (3S,11 E)- 14,16-dihydroxy-3-methyl-3,4,5,6,9, 10-hexahydro-1 H-2-benzoxacyclotetradecin-1 ,7(8H)-dione is/are an enzyme, preferably a lactonase.
  • Item 19 The method according to any one of items 9-18, wherein the compound is/are (E)-2,4-dihydroxy-6-(10-hydroxy-6-oxo-1-undecen-1-yl)benzoic acid and/or (E)-1-(3,5-dihydroxy- phenyl)-10-hydroxy-1-undecen-6-one.
  • R is selected from H and COOH; for reducing estrogenic effect(s) and/or endocrine impact(s) of a xenoestrogen.
  • composition e.g. nutritional composition
  • R is selected from H and COOH; for reducing estrogenic effect(s) and/or endocrine impact(s) of a composition (e.g. nutritional composition) comprising a xenoestrogen.
  • Item 22 The use according to any one of items 20-21 , wherein the xenoestrogen is a phytoestrogen, preferably an isoflavone, more preferably selected from genistein, daidzein, glycitein and equol.
  • the xenoestrogen is a phytoestrogen, preferably an isoflavone, more preferably selected from genistein, daidzein, glycitein and equol.
  • Item 23 The use according to any one of items 20-22, wherein the compound is/are (E)- 2,4-dihydroxy-6-(10-hydroxy-6-oxo-1-undecen-1-yl)benzoic acid and/or (E)-1-(3,5-dihydroxy- phenyl)-10-hydroxy-1-undecen-6-one.
  • Item 24 Composition, e.g. nutritional composition, for use in treatment, amelioration and/or prevention of symptoms associated with estrogenic effect(s) and/or endocrine impact(s) of a xenoestrogen;
  • composition comprises at least a compound having formula (I):
  • composition preferably wherein R is selected from H and COOH; and/or ii) wherein the composition comprises (3S,11 E)-14,16-dihydroxy-3-methyl-3,4,5,6,9,10- hexahydro-1 H-2-benzoxacyclotetradecin-1 ,7(8H)-dione; and means for converting (3S,11 E)- 14,16-dihydroxy-3-methyl-3,4,5,6,9, 10-hexahydro-1 H-2-benzoxacyclotetradecin-1 ,7(8H)-dione to a compound having formula (I):
  • Item 25 The composition for use according to item 24, wherein the means for converting (3S,11 E)-14,16-dihydroxy-3-methyl-3,4,5,6,9,10-hexahydro-1 H-2-benzoxacyclotetradecin- 1 ,7(8H)-dione is/are an enzyme, preferably a lactonase.
  • Item 26 The composition for use according to any one of items 24-25, wherein the compound is/are (E)-2,4-dihydroxy-6-(10-hydroxy-6-oxo-1-undecen-1-yl)benzoic acid and/or (E)- 1-(3,5-dihydroxy-phenyl)-10-hydroxy-1-undecen-6-one.
  • Item 27 The composition for use according to any one of items 24-26, wherein
  • composition is foodstuff; fodder; feed; silage; wet distillers grain; dried distillers grain with solubles; intermediate/s thereof; and/or mixture/s thereof; and/or wherein
  • the composition comprises cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • cereal(s) such as rice, wheat, rye, oats, corn or maize, barley, sorghum, and/or soy or other Fabaceae plant(s) suitable for human and/or animal consumption; and/or product(s) thereof.
  • Item 28 The composition for use according to any one of items 24-27, wherein the xenoestrogen is a phytoestrogen, preferably an isoflavone, more preferably an isoflavone selected from genistein, daidzein, glycitein and equol.
  • the xenoestrogen is a phytoestrogen, preferably an isoflavone, more preferably an isoflavone selected from genistein, daidzein, glycitein and equol.
  • Figure 1 shows the reduction of estrogenic effects of xenoestrogens upon addition of test substance 1 or 2 (TS1 or TS2, respectively). Estrogenic effects without added test substance (as indicated by "-") was set to 100%.
  • Ishikawa cells were incubated with said substance.
  • the Ishikawa cell line is a human endometrial adenocarcinoma cell line which represents a well-characterized estrogen-sensitive cell model and which produces both isoforms of the estrogen receptor, ERa and ERp.
  • Ishikawa cells are further known to show induction of gene expression encoding alkaline phosphatase (ALP) and thus stimulation of ALP activity, upon contact with estrogenic substance(s), e.g. Miller et al. 2016. Toxical. Sci. 154(1): 162-173; Albert et al. 1990. Cancer Res. 50(11): 3306-10.
  • ALP alkaline phosphatase
  • Ishikawa cells were seeded in assay medium at a concentration of 10000 cells per well. The cells were first grown for 48 h, and then incubated for additional 48 h with different concentrations of one substance or combinations of substances. Xenoestrogen substances and test substances were dissolved in DMSO and diluted in assay medium to a final concentration of 1% DMSO. A solvent control was performed by incubation with 1% DMSO in assay medium without any test substance. A positive control was performed by incubation with 1 nM of the estrogen-active hormone 17p-estradiol (E2). Experiments were performed in at least five independent biological replicates using different cell passages, with technical triplicates.
  • ALP activity was determined as the slope of the absorbance curve, wherein the slope of the curve obtained from the solvent control was set to 0% ALP activity, and the slope of the curve obtained from the positive control was set to 100% ALP activity.
  • a high ALP activity thus indicated high estrogenic effect.
  • test substance 1 compound having formula (I), wherein R is COOH
  • test substance 2 test substance 2

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Abstract

La présente invention concerne une composition comprenant un composé de formule (I), de préférence choisi parmi l'acide (E)-2,4-dihydroxy-6-(10-hydroxy-6-oxo-1-undécén-1-yl)benzoïque ou le (E)-1-(3,5-dihydroxy-phényl)-10-hydroxy-1-undécén-6-one, un procédé de réduction d'effet(s) oestrogénique(s) faisant appel audit composé, l'utilisation dudit composé, et une composition comprenant ledit composé pour son utilisation dans le traitement, l'atténuation et/ou la prévention de symptômes associés à un ou plusieurs effets oestrogéniques d'un xénoestrogène.
PCT/EP2024/072897 2023-08-17 2024-08-14 Moyens et procédés pour réduire l'effet oestrogénique d'un xénoestrogène Pending WO2025036933A1 (fr)

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