Black cohosh extracts and powders induce micronuclei, a biomarker of genetic damage, in human cells

Environmental and Molecular Mutagenesis

Volumn 59, Issue 5, 2018, Pages 416-426

  Smith Roe, Stephanie L ^a   Swartz, Carol D ^b   Shepard, Kim G ^b   Bryce, Steven M ^c   Dertinger, Stephen D ^c   Waidyanatha, Suramya ^a   Kissling, Grace E ^a   Auerbach, Scott S ^a   Witt, Kristine L ^a  

^a NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES   (United States)

^b INTEGRATED LABORATORY SYSTEMS   (United States)

^c LITRON LABORATORIES   (United States)

Author keywords

Actaea racemosa; aneugen; dietary supplement; folic acid; micronucleus assay

Indexed keywords

CIMICIFUGA RACEMOSA EXTRACT; FOLIC ACID; BIOLOGICAL MARKER; MUTAGENIC AGENT;

ACTAEA RACEMOSA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CELL DIVISION; CHEMICAL COMPOSITION; CONTROLLED STUDY; CYTOTOXICITY; DIETARY SUPPLEMENT; DRUG CYTOTOXICITY; ERYTHROCYTE; FEMALE; FOLATE METABOLISM; GENETIC DAMAGE; GENOTOXICITY; HUMAN; HUMAN CELL; IN VITRO STUDY; LYMPHOBLASTOID CELL; MACROCYTIC ANEMIA; MEGALOBLASTIC ANEMIA; MICRONUCLEUS; MICRONUCLEUS TEST; MUTAGENICITY; NONHUMAN; POWDER; RAT; TOXICITY TESTING; ACTAEA; ANIMAL; CELL LINE; CHEMICALLY INDUCED; DNA DAMAGE; DOSE RESPONSE; DRUG EFFECT; METABOLISM; MOUSE; PATHOLOGY;

ANEMIA, MEGALOBLASTIC; ANIMALS; BIOMARKERS; CELL LINE; CIMICIFUGA; DIETARY SUPPLEMENTS; DNA DAMAGE; DOSE-RESPONSE RELATIONSHIP, DRUG; ERYTHROCYTES; FOLIC ACID; HUMANS; MICE; MICRONUCLEI, CHROMOSOME-DEFECTIVE; MICRONUCLEUS TESTS; MUTAGENS; RATS;

EID: 85045705374     PISSN: 08936692     EISSN: 10982280     Source Type: Journal    
DOI: 10.1002/em.22182     Document Type: Article

References (46)

1. Abdel-Rahman A, Anyangwe N, Carlacci L, Casper S, Danam RP, Enongene E, Erives G, Fabricant D, Gudi R, Hilmas CJ, Hines F, Howard P, Levy D, Lin Y, Moore RJ, Pfeiler E, Thurmond TS, Turujman S, Walker NJ. 2011. The safety and regulation of natural products used as foods and food ingredients. Toxicol Sci 123:333–348
2. Beetstra S, Thomas P, Salisbury C, Turner J, Fenech M. 2005. Folic acid deficiency increases chromosomal instability, chromosome 21 aneuploidy and sensitivity to radiation-induced micronuclei. Mutat Res 578:317–326
3. Blount BC, Ames BN. 1995. DNA damage in folate deficiency. Baillieres Clin Haematol 8:461–478
4. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN. 1997. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 94:3290–3295
5. Bose S, Kalra S, Yammani RR, Ahuja R, Seetharam B. 2007. Plasma membrane delivery, endocytosis and turnover of transcobalamin receptor in polarized human intestinal epithelial cells. J Physiol 581:457–466
6. Bryce SM, Bernacki DT, Bemis JC, Dertinger SD. 2016. Genotoxic mode of action predictions from a multiplexed flow cytometric assay and a machine learning approach. Environ Mol Mutagen 57:171–189
7. Bryce SM, Bernacki DT, Bemis JC, Spellman RA, Engel ME, Schuler M, Lorge E, Heikkinen PT, Hemmann U, Thybaud V, Wilde S, Queisser N, Sutter A, Zeller A, Guérard M, Kirkland D, Dertinger SD. 2017. Interlaboratory evaluation of a multiplexed high information content in vitro genotoxicity assay. Environ Mol Mutagen 58:146–161
8. Cora MC, Gwinn W, Wilson R, King D, Waidyanatha S, Kissling GE, Brar SS, Olivera D, Blystone C, Travlos G. 2017. A black cohosh extract causes hematologic and biochemical changes consistent with a functional cobalamin deficiency in female B6C3F1/N mice. Toxicol Pathol 45:614–623
9. Cordell GA, Quinn-Beattie ML, Farnsworth NR. 2001. The potential of alkaloids in drug discovery. Phytother Res 15:183–205
10. Das KC, Mohanty D, Garewal G. 1986. Cytogenetics in nutritional megaloblastic anaemia: Prolonged persistence of chromosomal abnormalities in lymphocytes after remission. Acta Haematol 76:146–154
11. Dietary Supplement Health and Education Act of 1994. 1994. Public Law 103–417, 103RD Congress. https://ods.od.nih.gov/About/DSHEA_Wording.aspx (accessed October 19, 2017)
12. Duthie SJ. 1999. Folic acid deficiency and cancer: Mechanisms of DNA instability. Br Med Bull 55:578–592
13. Duthie SJ, Hawdon A. 1998. DNA instability (strand breakage, uracil misincorporation, and defective repair) is increased by folic acid depletion in human lymphocytes in vitro. FASEB J 12:1491–1497
14. Duthie SJ, McMillan P. 1997. Uracil misincorporation in human DNA detected using single cell gel electrophoresis. Carcinogenesis 18:1709–1714
15. Einbond LS, Soffritti M, Esposti DD, Wu HA, Tibaldi E, Lauriola M, He K, Park T, Su T, Huggins L, Wang X, Roller M, Brennan R. 2012. Pharmacological mechanisms of black cohosh in Sprague-Dawley rats. Fitoterapia 83:461–468
16. Einer-Jensen N, Zhao J, Andersen KP, Kristoffersen K. 1996. Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats. Maturitas 25:149–153
17. Everson RB, Wehr CM, Erexson GL, MacGregor JT. 1988. Association of marginal folate depletion with increased human chromosomal damage in vivo: Demonstration by analysis of micronucleated erythrocytes. J Natl Cancer Inst 80:525–529
18. Fenech M. 1999. Micronucleus frequency in human lymphocytes is related to plasma vitamin B12 and homocysteine. Mutat Res 428:299–304
19. Gafner S. 2016. On adulteration of Actaea racemosa. Botanical Adulterants Bulletin. http://cms.herbalgram.org/BAP/pdf/BAP-BABs-BlackCohosh-FINAL_copy1.pdf (accessed 19 October, 2017)
20. Heath CW. Jr. 1966. Cytogenetic observations in vitamin B12 and folate deficiency. Blood 27:800–815
21. IARC Working Group. 1993. Caffeic acid. IARC Monogr Eval Carcinog Risks Hum 56:115–134
22. Jiang B, Ma C, Motley T, Kronenberg F, Kennelly EJ. 2011. Phytochemical fingerprinting to thwart black cohosh adulteration: A 15 Actaea species analysis. Phytochem Anal 22:339–351
23. Laakmann E, Grajecki D, Doege K, zu Eulenburg C, Buhling KJ. 2012. Efficacy of Cimicifuga racemosa, Hypericum perforatum and Agnus castus in the treatment of climacteric complaints: A systematic review. Gynecol Endocrinol 28:703–709
24. Leite C, Hoogstraten B. 1977. Differential diagnosis of anemia and cancer. CA Cancer J Clin 27:88–99
25. Lupu R, Mehmi I, Atlas E, Tsai MS, Pisha E, Oketch-Rabah HA, Nuntanakorn P, Kennelly EJ, Kronenberg F. 2003. Black cohosh, a menopausal remedy, does not have estrogenic activity and does not promote breast cancer cell growth. Int J Oncol 23:1407–1412
26. MacGregor JT, Wehr CM, Hiatt RA, Peters B, Tucker JD, Langlois RG, Jacob RA, Jensen RH, Yager JW, Shigenaga MK, Frei B, Eynon BP, Ames BN. 1997. ‘Spontaneous’ genetic damage in man: Evaluation of interindividual variability, relationship among markers of damage, and influence of nutritional status. Mutat Res 377:125–135
27. Maistro EL, Angeli JP, Andrade SF, Mantovani MS. 2011. In vitro genotoxicity assessment of caffeic, cinnamic and ferulic acids. Genet Mol Res 10:1130–1140
28. Majer BJ, Mersch-Sundermann V, Darroudi F, Laky B, de Wit K, Knasmuller S. 2004. Genotoxic effects of dietary and lifestyle related carcinogens in human derived hepatoma (HepG2, Hep3B) cells. Mutat Res 551:153–166
29. Mercado-Feliciano M, Cora MC, Witt KL, Granville CA, Hejtmancik MR, Fomby L, Knostman KA, Ryan MJ, Newbold R, Smith C, Foster PM, Vallant MK, Stout MD. 2012. An ethanolic extract of black cohosh causes hematological changes but not estrogenic effects in female rodents. Toxicol Appl Pharmacol 263:138–147
30. MRC Vitamin Study Research Group. 1991. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 338:131–137
31. Ni J, Lu L, Fenech M, Wang X. 2010. Folate deficiency in human peripheral blood lymphocytes induces chromosome 8 aneuploidy but this effect is not modified by riboflavin. Environ Mol Mutagen 51:15–22
32. Nikolic D, Lankin DC, Cisowska T, Chen SN, Pauli GF, van Breemen RB. 2015. Nitrogen-containing constituents of black cohosh: chemistry, structure elucidation, and biological activities. Recent Adv Phytochem 45:31–75
33. National Toxicology Program (NTP). 2017. National Toxicology Program (NTP) Botanical Dietary Supplements Research Program. https://ntp.niehs.nih.gov/results/areas/botanical/index.html (accessed 19 October, 2017)
34. National Toxicology Program (NTP) Chemical Effects in Biological Systems (CEBS). 2017. Website. https://tools.niehs.nih.gov/cebs3/ui/ (accessed 19 October, 2017)
35. Rachon D, Vortherms T, Seidlova-Wuttke D, Wuttke W. 2008. Effects of black cohosh extract on body weight gain, intra-abdominal fat accumulation, plasma lipids and glucose tolerance in ovariectomized Sprague-Dawley rats. Maturitas 60:209–215
36. Reagan-Shaw S, Nihal M, Ahmad N. 2008. Dose translation from animal to human studies revisited. FASEB J 22:659–661
37. Reame NE, Lukacs JL, Padmanabhan V, Eyvazzadeh AD, Smith YR, Zubieta JK. 2008. Black cohosh has central opioid activity in postmenopausal women: Evidence from naloxone blockade and positron emission tomography neuroimaging. Menopause 15:832–840
38. Rhyu MR, Lu J, Webster DE, Fabricant DS, Farnsworth NR, Wang ZJ. 2006. Black cohosh (Actaea racemosa, Cimicifuga racemosa) behaves as a mixed competitive ligand and partial agonist at the human mu opiate receptor. J Agric Food Chem 54:9852–9857
39. Seidlova-Wuttke D, Hesse O, Jarry H, Christoffel V, Spengler B, Becker T, Wuttke W. 2003. Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimicifuga racemosa) extract: Comparison with estradiol-17beta. Eur J Endocrinol 149:351–362
40. Stich HF, Rosin MP, Wu CH, Powrie WD. 1981. The action of transition metals on the genotoxicity of simple phenols, phenolic acids and cinnamic acids. Cancer Lett 14:251–260
41. Stopa EG, O'Brien R, Katz M. 1979. Effect of colchicine on guinea pig intrinsic factor-vitamin B12 receptor. Gastroenterology 76:309–314
42. Wang X, Thomas P, Xue J, Fenech M. 2004. Folate deficiency induces aneuploidy in human lymphocytes in vitro-evidence using cytokinesis-blocked cells and probes specific for chromosomes 17 and 21. Mutat Res 551:167–180
43. Wang YJ, Dou J, Cross KP, Valerio LG. Jr. 2011. Computational analysis for hepatic safety signals of constituents present in botanical extracts widely used by women in the United States for treatment of menopausal symptoms. Regul Toxicol Pharmacol 59:111–124
44. Wickramasinghe SN. 1995. Morphology, biology and biochemistry of cobalamin- and folate-deficient bone marrow cells. Baillieres Clin Haematol 8:441–459
45. Wickramasinghe SN. 2006. Diagnosis of megaloblastic anaemias. Blood Rev 20:299–318
46. Zhang J, Bai W, Wang W, Jiang H, Jin B, Liu Y, Liu S, Wang K, Jia J, Qin L. 2017. Mechanisms underlying alterations in norepinephrine levels in the locus coeruleus of ovariectomized rats: Modulation by estradiol valerate and black cohosh. Neuroscience 354:110–121