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Toxicological evaluation of the natural products and some semisynthetic derivatives of Heterotheca inuloides Cass (Asteraceae).
J Ethnopharmacol. 2015 Dec 04; 175:256-65.JE

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

Heterotheca ineuloides Cass (Asteraceae), popularly known as árnica mexicana, is widely used in Mexican traditional medicine to treat bruises, dermatological problems, rheumatic pains, and other disorders as cancer. The major constituents in H. inuloides are cadinane type sesquiterpenes, flavonoids and phytosterols. Compounds with a cadinane skeleton have been proved to possess cytotoxic activity against human-tumor cell lines and brine shrimp, and display toxic effects in different animal species. Although this plant has been widely used, there is little available information on the safety and toxicity especially of pure compounds.

AIM OF THIS STUDY

Evaluate the potential toxicity of the natural products isolated from H. inuloides and some semisynthetic derivatives.

MATERIALS AND METHODS

The toxic aspects of the following natural products isolated from dried flowers of H. inuloides: 7-hydroxy-3,4-dihydrocadalene (1), 7-hydroxycadalene (2), 3,7-dihydroxy-3(4H)-isocadalen-4-one (3), (1R,4R)-1-hydroxy-4H-1,2,3,4- tetrahydrocadalen-15-oic acid (4), D-chiro-inositol (5), quercetin (6), quercetin-3,7,3'-trimethyl ether (7), quercetin-3,7,3',4'-tetramethyl ether (8), eriodictyol-7,4'-dimethyl ether (9), α-spinasterol (10), caryolan-1,9β-diol (11) and 7-(3,3-dimethylallyloxy)-coumarin (12) as well as the toxic aspects of the semisynthetic compounds 7-acetoxy-3,4-dihydrocadalene (13), 7-benzoxy-3,4-dihydrocadalene (14), 7-acetoxycadalene (15), 7-benzoxycadalene (16), quercetin pentaacetate (17), 7-hydroxycalamenene (18), 3,8-dimethyl-5-(1-methylethyl)-1,2-naphthoquinone (19), and 4-isopropyl-1,6-dimethylbenzo[c]oxepine-7,9-dione (20). Toxic activities of compounds were determined by sulforhodamine B (SRB) assay, Artemia salina assay, RAW264.7 macrophage cells. Additionally, the acute toxicity in mouse of compound 1, the major natural sesquiterpene isolated from the acetone extract, was evaluated.

RESULTS

The best cytotoxicity activity was observed for mansonone C (19) on K562 cell line with IC50 1.45 ± 0.14 μM, for 7-hydroxycadalene (2) on HCT-15 cell line with IC50 18.89 ± 1.2 μM, and for quercetin pentaacetate (17) on MCF-7 cell line with IC50 22.57 ± 2.4 μM. Sesquiterpenes mansonone C (19) and 7-hydroxy-3,4-dihydrocadalene (1) caused the strongest deleterious effects against A. salina with IC50 39.4 ± 1.07, and 45.47 ± 1.74 μM, respectively. The number of viable RAW 264.7 cells was reduced with sesquiterpenes 1 and 2 by more than 90%. In addition, the acute study of 1 revealed no lethal effects at 300 mg/kg body weight, however, a reduction in the body weight of mice, morphological changes in the tissues of the liver and kidney and toxic signs were observed at very high doses (2000 mg/kg).

CONCLUSION

The results provided evidence for the cytotoxicity of Mexican arnica (H. inuloides) metabolites and may be correlated with one of the popular uses of this plant, in traditional Mexican medicine, as anticancer remedy. Among the active compounds contained in the acetone extract, the cytotoxic activity is mainly ascribable to cadinene type sesquiterpenes. In addition, evidence of acute toxicity suggests that 7-hydroxy-3,4-dihydrocadalene (1) may lead to toxicity at very high doses.

Authors+Show Affiliations

Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán, 04510 México D.F., Mexico.Laboratorio de Neuroquímica, Instituto Nacional de Pediatría, Insurgentes Sur 3700C Insurgentes Cuicuilco, Coyoacán, 04530 México D.F., Mexico.Departamento de Patología, Instituto Nacional de Pediatría, Insurgentes Sur 3700C Insurgentes Cuicuilco, Coyoacán, 04530 México D.F., Mexico.Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán, 04510 México D.F., Mexico.Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán, 04510 México D.F., Mexico. Electronic address: delgado@unam.mx.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26344038

Citation

Rodríguez-Chávez, José Luis, et al. "Toxicological Evaluation of the Natural Products and some Semisynthetic Derivatives of Heterotheca Inuloides Cass (Asteraceae)." Journal of Ethnopharmacology, vol. 175, 2015, pp. 256-65.
Rodríguez-Chávez JL, Coballase-Urrutia E, Sicilia-Argumedo G, et al. Toxicological evaluation of the natural products and some semisynthetic derivatives of Heterotheca inuloides Cass (Asteraceae). J Ethnopharmacol. 2015;175:256-65.
Rodríguez-Chávez, J. L., Coballase-Urrutia, E., Sicilia-Argumedo, G., Ramírez-Apan, T., & Delgado, G. (2015). Toxicological evaluation of the natural products and some semisynthetic derivatives of Heterotheca inuloides Cass (Asteraceae). Journal of Ethnopharmacology, 175, 256-65. https://doi.org/10.1016/j.jep.2015.08.055
Rodríguez-Chávez JL, et al. Toxicological Evaluation of the Natural Products and some Semisynthetic Derivatives of Heterotheca Inuloides Cass (Asteraceae). J Ethnopharmacol. 2015 Dec 4;175:256-65. PubMed PMID: 26344038.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Toxicological evaluation of the natural products and some semisynthetic derivatives of Heterotheca inuloides Cass (Asteraceae). AU - Rodríguez-Chávez,José Luis, AU - Coballase-Urrutia,Elvia, AU - Sicilia-Argumedo,Gloria, AU - Ramírez-Apan,Teresa, AU - Delgado,Guillermo, Y1 - 2015/09/05/ PY - 2015/05/26/received PY - 2015/08/06/revised PY - 2015/08/30/accepted PY - 2015/9/8/entrez PY - 2015/9/8/pubmed PY - 2016/9/28/medline KW - 3,8-dimethyl-5-(1-methylethyl)-1,2-naphthoquinone (PubChem CID: 21742) KW - 7-(3,3-dimethylallyloxy)-coumarin (PubChem CID: 320362) KW - 7-hydroxy-3,4-dihydrocadalene (PubChem CID: 163563874) KW - 7-hydroxycadalene (PubChem CID: 608115) KW - Acute toxicity KW - Cadinanes KW - Cytotoxicity KW - Heterotheca inuloides KW - Mexican arnica KW - RAW264.7 macrophages KW - eriodictyol-7,4′-dimethyl ether (PubChem CID: 320054) KW - quercetin (PubChem CID: 5280343) KW - quercetin pentaacetate (PubChem CID: 14005) KW - quercetin-3,7,3′,4′-tetramethyl ether (PubChem CID: 5352005) KW - quercetin-3,7,3′-trimethyl ether (PubChem CID: 12303) KW - α-spinasterol (PubChem CID: 5281331) SP - 256 EP - 65 JF - Journal of ethnopharmacology JO - J Ethnopharmacol VL - 175 N2 - ETHNOPHARMACOLOGICAL RELEVANCE: Heterotheca ineuloides Cass (Asteraceae), popularly known as árnica mexicana, is widely used in Mexican traditional medicine to treat bruises, dermatological problems, rheumatic pains, and other disorders as cancer. The major constituents in H. inuloides are cadinane type sesquiterpenes, flavonoids and phytosterols. Compounds with a cadinane skeleton have been proved to possess cytotoxic activity against human-tumor cell lines and brine shrimp, and display toxic effects in different animal species. Although this plant has been widely used, there is little available information on the safety and toxicity especially of pure compounds. AIM OF THIS STUDY: Evaluate the potential toxicity of the natural products isolated from H. inuloides and some semisynthetic derivatives. MATERIALS AND METHODS: The toxic aspects of the following natural products isolated from dried flowers of H. inuloides: 7-hydroxy-3,4-dihydrocadalene (1), 7-hydroxycadalene (2), 3,7-dihydroxy-3(4H)-isocadalen-4-one (3), (1R,4R)-1-hydroxy-4H-1,2,3,4- tetrahydrocadalen-15-oic acid (4), D-chiro-inositol (5), quercetin (6), quercetin-3,7,3'-trimethyl ether (7), quercetin-3,7,3',4'-tetramethyl ether (8), eriodictyol-7,4'-dimethyl ether (9), α-spinasterol (10), caryolan-1,9β-diol (11) and 7-(3,3-dimethylallyloxy)-coumarin (12) as well as the toxic aspects of the semisynthetic compounds 7-acetoxy-3,4-dihydrocadalene (13), 7-benzoxy-3,4-dihydrocadalene (14), 7-acetoxycadalene (15), 7-benzoxycadalene (16), quercetin pentaacetate (17), 7-hydroxycalamenene (18), 3,8-dimethyl-5-(1-methylethyl)-1,2-naphthoquinone (19), and 4-isopropyl-1,6-dimethylbenzo[c]oxepine-7,9-dione (20). Toxic activities of compounds were determined by sulforhodamine B (SRB) assay, Artemia salina assay, RAW264.7 macrophage cells. Additionally, the acute toxicity in mouse of compound 1, the major natural sesquiterpene isolated from the acetone extract, was evaluated. RESULTS: The best cytotoxicity activity was observed for mansonone C (19) on K562 cell line with IC50 1.45 ± 0.14 μM, for 7-hydroxycadalene (2) on HCT-15 cell line with IC50 18.89 ± 1.2 μM, and for quercetin pentaacetate (17) on MCF-7 cell line with IC50 22.57 ± 2.4 μM. Sesquiterpenes mansonone C (19) and 7-hydroxy-3,4-dihydrocadalene (1) caused the strongest deleterious effects against A. salina with IC50 39.4 ± 1.07, and 45.47 ± 1.74 μM, respectively. The number of viable RAW 264.7 cells was reduced with sesquiterpenes 1 and 2 by more than 90%. In addition, the acute study of 1 revealed no lethal effects at 300 mg/kg body weight, however, a reduction in the body weight of mice, morphological changes in the tissues of the liver and kidney and toxic signs were observed at very high doses (2000 mg/kg). CONCLUSION: The results provided evidence for the cytotoxicity of Mexican arnica (H. inuloides) metabolites and may be correlated with one of the popular uses of this plant, in traditional Mexican medicine, as anticancer remedy. Among the active compounds contained in the acetone extract, the cytotoxic activity is mainly ascribable to cadinene type sesquiterpenes. In addition, evidence of acute toxicity suggests that 7-hydroxy-3,4-dihydrocadalene (1) may lead to toxicity at very high doses. SN - 1872-7573 UR - https://www.unboundmedicine.com/medline/citation/26344038/Toxicological_evaluation_of_the_natural_products_and_some_semisynthetic_derivatives_of_Heterotheca_inuloides_Cass__Asteraceae__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-8741(15)30121-5 DB - PRIME DP - Unbound Medicine ER -