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LE Magazine January 2006
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I3C & DIM

Natural, Dual-Action Protection Against Deadly Cancers By Dale Kiefer

Cancer-Fighting Watercress and Broccoli

An often overlooked member of the cruciferous vegetable family, watercress is an “exceptionally rich source”59 of potent cancer-fighting isothiocyanates, including a much-studied compound known as phenethyl isothiocyanate, or PEITC.

Recently published research indicates that an extract of the cruciferous vegetables watercress and broccoli suppresses an enzyme closely associated with the invasive potential of breast cancer.60 Scientists working with breast cancer cell cultures observed that a broccoli-watercress extract effectively lowers the expression of metalloproteinase-9, an enzyme associated with breast cancer’s invasiveness. The same team simultaneously published research indicating that isothiocyanate compounds in watercress suppress production of pro-inflammatory compounds in laboratory models of cellular activity. “Overproduction of both nitric oxide (NO) and prostaglandins (PGE) has been associated with numerous pathological conditions, including chronic inflammation and cancer,” the researchers noted. They speculated that this effect may contribute to the anti-cancer activity of cruciferous vegetables.61

For men, PEITC has particular value in preventing prostate cancer. Noting that epidemiological evidence shows a strong association between greater intake of cruciferous vegetables and reduced risk of prostate cancer, scientists in New York sought to identify the specific compounds responsible for cancer prevention. They found that a conjugate of PEITC, which is abundant in watercress, inhibited proliferation and tumorigenesis of prostate cancer cells growing in culture.62

Oncology researchers and physicians are becoming interested in watercress’s potential use against deadly lung cancer.63 Research shows that watercress-derived PEITC is a protective agent against lung cancer in laboratory rodents.64,65 Subsequent research continues to confirm and expand on these findings.66,67

Remarkably, research shows that even after isothiocyanates such as PEITC are modified for efficient removal from the body in urine, they remain active against cancer. Urine containing conjugated isothiocyanates, which are stored in the bladder while awaiting removal, acts on the tissue lining the bladder to prevent carcinoma. This is precisely the site where most bladder tumors arise. “Development of effective preventive strategies for bladder cancer is of critical importance,” one research team recently noted, concluding that isothiocyanates such as those in watercress “may be especially useful for the prevention of bladder cancer.”68

Adding another piece to the puzzle, scientists at the University of Arizona determined in 2003 that PEITC inhibits cancer cell proliferation with surprising rapidity. This is significant, they noted, because PEITC and other dietary isothiocyanates from cruciferous vegetables tend to be cleared from the body through urinary excretion. Working with human leukemia cells, they discovered that isothiocyanates, including PEITC, were able to limit cancer cell proliferation.69 After only three hours of exposure to PEITC and other cruciferous isothiocyanates, the cancer cells experienced the full spectrum of PEITC’s anti-cancer effects.

French scientists recently discovered that compounds in watercress are adept at inducing both phase I and phase II enzymes, an effect that may explain its ability to inhibit chemically induced DNA damage from a wide variety of compounds. DNA damage can lead to carcinogenesis.70

PROTECTING AGAINST HORMONE-INDUCED BREAST CANCER

Breast cancer is the most common cancer, and the second leading cause of cancer-related death, in women. Many factors such as age, genetics, alcohol intake, and level of physical activity influence breast cancer risk.55

Hormones also play a crucial role in influencing breast cancer risk. After noting that women who experience early menarche (onset of menstruation) or late menopause have an increased risk of breast cancer, scientists have proposed that a woman’s cumulative lifetime exposure to hormones helps determine her risk of developing breast cancer. Furthermore, the long-term use of hormone replacement therapy with conjugated equine estrogens combined with synthetic progestins is also known to increase breast cancer risk.55

One of the most important applications of I3C and DIM may be in protecting against hormone-induced breast cancer. Epidemiological, laboratory, and animal studies indicate that dietary intake of I3C prevents the development of estrogen-enhanced cancers, including breast, endometrial, and cervical cancers. While estrogen increases the growth and survival of tumors, I3C has been found to cause growth arrest and increased apoptosis (programmed cell death).56

Both I3C and DIM help promote healthy metabolism of estrogen by influencing the ratio of beneficial 2-hydroxyestrone to unfavorable 16-alpha-hydroxyestrone.48,50 An increased ratio of these estrogen metabolites is associated with a decreased risk of breast and other cancers.39,47-53 A placebo-controlled, double-blind study of women at increased risk for breast cancer found that four weeks of supplementation with I3C promoted favorable changes in the urinary estrogen metabolite ratio of 2-hydroxy-estrone to 16-alpha-hydroxyestrone.50

A recent pilot study examined DIM’s effects on estrogen metabolites in postmenopausal women with a history of early-stage breast cancer. After one month of supplementation with DIM, the participants demonstrated a significant increase in levels of beneficial 2-hydroxyestrone and an insignificant increase in the ratio of 2-hydroxyestrone to 16-alpha-hydroxy-estrone. These results suggest that DIM may play a role in preventing breast cancer reoccurrence by promoting healthy estrogen metabolism.48

A clinical trial assessing I3C’s role in preventing cancer in healthy individuals is currently under way.57 Several clinical trials investigating DIM’s cancer-preventive and therapeutic potential are also in progress.58

Carnosic Acid and Vitamin D

Cancer researchers have been paying a lot of attention to vitamin D. Scientists know that vitamin D functions as a hormone, affecting immune response and acting in various ways to protect against cancer.71-74 Vitamin D is available in foods and supplements, as well as through its naturally occurring activation in the skin following exposure to ultraviolet light (sunlight). Vitamin D thus appears to be very important to the body’s innate ability to fight cancer.75,76

To complement vitamin’s D anti-cancer role, a compound derived from the culinary herb rosemary (Rosmarinus officinalis) acts to enhance vitamin D’s biochemical activity. Carnosic acid and carnosol, found in rosemary, are antioxidant polyphenols that have been shown to aid vitamin D’s efforts to thwart cancer. Rather than killing cancer cells outright as many chemotherapeutic agents do, vitamin D halts cancer by forcing precancerous cells to differentiate or become, in essence, more mature cells.77,78 Because cancer is characterized by less mature cells, a process that compels these cells to become more mature is beneficial to fighting cancer. Scientists therefore are keenly interested in using supplemental vitamin D for differentiation therapy to prevent and possibly treat cancer.

Beyond this promising partnership with natural vitamin D, researchers have identified other mechanisms by which carnosic acid and carnosol work to protect and enhance the immune system.79 These powerful natural antioxidants exhibit antibacterial activity, even against problematic bacteria that have developed resistance to standard antibiotics.80 Carnosol has demonstrated activity against the HIV virus, at concentrations that were not harmful to healthy cells.81 Much like I3C and DIM, rosemary compounds have also been shown to reduce the carcinogenic potential of natural estrogens by enhancing their metabolism in the liver. When treated with a diet containing 2% rosemary for three weeks, female mice increased their beneficial 2-hydroxylation of estrogens by approximately 150% while inhibiting the detrimental 16-alpha-hydroxylation of estradiol by approximately 50%.82

Glucosinolates and their derivatives from cruciferous vegetables, along with the powerful cancer-fighting compound carnosic acid from rosemary, have thus been shown to be powerful weapons in the battle against cancer.

References

1. Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 2005 Sep;4(9):1201-15.

2. Sarkar FH, Li Y. Indole-3-carbinol and prostate cancer. J Nutr. 2004 Dec;134(12 Suppl):3493S-8S.

3. Plate AY, Gallaher DD. Effects of indole-3-carbinol and phenethyl isothiocyanate on colon carcinogenesis induced by azoxymethane in rats. Carcinogenesis. 2005 Aug 19.

4. Bonnesen C, Eggleston IM, Hayes JD. Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res. 2001 Aug 15;61(16):6120-30.

5. Tadi K, Chang Y, Ashok BT, et al. 3,3’-Diindolylmethane, a cruciferous vegetable derived synthetic anti-proliferative compound in thyroid disease. Biochem Biophys Res Commun. 2005 Nov 25;337(3):1019-25.

6. Kim YS, Milner JA. Targets for indole-3-carbinol in cancer prevention. J Nutr Biochem. 2005 Feb;16(2):65-73.

7. Brew CT, Aronchik I, Hsu JC, et al. Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. Int J Cancer. 2005 Sep 8.

8. Chang X, Tou JC, Hong C, et al. 3,3’-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice. Carcinogenesis. 2005 Apr;26(4):771-8.

9. Manson MM, Farmer PB, Gescher A, Steward WP. Innovative agents in cancer prevention. Recent Results Cancer Res. 2005;166:257-75.

10. Shukla Y, Kalra N, Katiyar S, Siddiqui IA, Arora A. Chemopreventive effect of indole-3-carbinol on induction of preneoplastic altered hepatic foci. Nutr Cancer. 2004;50(2):214-20.

11. Garikapaty VP, Ashok BT, Chen YG, et al. Anti-carcinogenic and anti-metastatic properties of indole-3-carbinol in prostate cancer. Oncol Rep. 2005 Jan;13(1):89-93.

12. Rahman KW, Sarkar FH. Inhibition of nuclear translocation of nuclear factor-{kappa}B contributes to 3,3’-diindolylmethane-induced apoptosis in breast cancer cells. Cancer Res. 2005 Jan 1;65(1):364-71.

13. Available at: http://www.cancer.org/docroot/ CRI/content/CRI_2_4_2x_What_are_the_risk_factors_for_cancer_72.asp?sitearea. Accessed October 31, 2005.

14. Available at: http://www.cancer.org/downloads/stt/ Estimated_New_Cancer_Cases_and_Deaths_by_Sex_for_All_Sites,_US,_2005.pdf. Accessed October 31, 2005.

15. Li Y, Chinni SR, Sarkar FH. Selective growth regulatory and pro-apoptotic effects of DIM is mediated by AKT and NF-kappaB pathways in prostate cancer cells. Front Biosci. 2005 Jan 1;10:236-43.

16. Fowke JH, Chung FL, Jin F, et al. Urinary isothiocyanate levels, brassica, and human breast cancer. Cancer Res. 2003 Jul 15;63(14):3980-6.

17. Rouzaud G, Young SA, Duncan AJ. Hydrolysis of glucosinolates to isothiocyanates after ingestion of raw or microwaved cabbage by human volunteers. Cancer Epidemiol Biomarkers Prev. 2004 Jan;13(1):125-31.

18. Getahun SM, Chung FL. Conversion of glucosinolates to isothiocyanates in humans after ingestion of cooked watercress. Cancer Epidemiol Biomarkers Prev. 1999 May;8(5):447-51.

19. Johnson IT. Glucosinolates: bioavailability and importance to health. Int J Vitam Nutr Res. 2002 Jan;72(1):26-31.

20. Reed GA, Peterson KS, Smith HJ, et al. A phase I study of indole-3-carbinol in women: tolerability and effects. Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):1953-60.

21. Leibelt DA, Hedstrom OR, Fischer KA, Pereira CB, Williams DE. Evaluation of chronic dietary exposure to indole-3-carbinol and absorption-enhanced 3,3’-diindolylmethane in sprague-dawley rats. Toxicol Sci. 2003 Jul;74(1):10-21.

22. Bradlow HL, Michnovicz JJ, Halper M, et al. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiol Biomarkers Prev. 1994 Oct;3(7):591-5.

23. Ashok BT, Chen Y, Liu X, et al. Abrogation of estrogen-mediated cellular and biochemical effects by indole-3-carbinol. Nutr Cancer. 2001;41(1-2):180-7.

24. Ashok BT, Chen YG, Liu X, et al. Multiple molecular targets of indole-3-carbinol, a chemopreventive anti-estrogen in breast cancer. Eur J Cancer Prev. 2002 Aug;11 Suppl 2S86-S93.

25. Yuan F, Chen DZ, Liu K, et al. Anti-estrogenic activities of indole-3-carbinol in cervical cells: implication for prevention of cervical cancer. Anticancer Res. 1999 May;19(3A):1673-80.

26. Liu H, Wormke M, Safe SH, Bjeldanes LF. Indolo[3,2-b]carbazole: a dietary-derived factor that exhibits both antiestrogenic and estrogenic activity. J Natl Cancer Inst. 1994 Dec 7;86(23):1758-65.

27. Firestone GL, Bjeldanes LF. Indole-3-carbinol and 3-3’-diindolylmethane antiproliferative signaling pathways control cell-cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. J Nutr. 2003 Jul;133(7 Suppl):2448S-55S.

28. Sarkar FH, Rahman KM, Li Y. Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells. J Nutr. 2003 Jul;133(7 Suppl):2434S-9S.

29. Nachshon-Kedmi M, Yannai S, Haj A, Fares FA. Indole-3-carbinol and 3,3’-diindolylmethane induce apoptosis in human prostate cancer cells. Food Chem Toxicol. 2003 Jun;41(6):745-52.

30. Crowell JA, Page JG, Levine BS, Tomlinson MJ, Hebert CD. Indole-3-carbinol, but not its major digestive product 3,3’-diindolylmethane, induces reversible hepatocyte hypertrophy and cytochromes P450. Toxicol Appl Pharmacol. 2005 Jul 22.

31. Larsen-Su S, Williams DE. Dietary indole-3-carbinol inhibits FMO activity and the expression of flavin-containing monooxygenase form 1 in rat liver and intestine. Drug Metab Dispos. 1996 Sep;24(9):927-31.

32. Wu HT, Lin SH, Chen YH. Inhibition of cell proliferation and in vitro markers of angiogenesis by indole-3-carbinol, a major indole metabolite present in cruciferous vegetables. J Agric Food Chem. 2005 Jun 29;53(13):5164-9.

33. Chatterji U, Riby JE, Taniguchi T, et al. Indole-3-carbinol stimulates transcription of the interferon gamma receptor 1 gene and augments interferon responsiveness in human breast cancer cells. Carcinogenesis. 2004 Jul;25(7):1119-28.

34. Carter TH, Liu K, Ralph W, Jr, et al. Diindolylmethane alters gene expression in human keratinocytes in vitro. J Nutr. 2002 Nov;132(11):3314-24.

35. Auborn KJ, Fan S, Rosen EM, et al. Indole-3-carbinol is a negative regulator of estrogen. J Nutr. 2003 Jul;133(7 Suppl):2470S-5S.

36. Xue L, Firestone GL, Bjeldanes LF. DIM stimulates IFNgamma gene expression in human breast cancer cells via the specific activation of JNK and p38 pathways. Oncogene. 2005 Mar 31;24(14):2343-53.

37. Sun S, Han J, Ralph WM, Jr, et al. Endoplasmic reticulum stress as a correlate of cytotoxicity in human tumor cells exposed to diindolylmethane in vitro. Cell Stress Chaperones. 2004 Mar;9(1):76-87.

38. Available at: http://www.cancer.gov/ncicancerbulletin/NCI_Cancer_Bulletin_051005/page4. Accessed November 3, 2005.

39. Muti P, Bradlow HL, Micheli A, et al. Estrogen metabolism and risk of breast cancer: a prospective study of the 2:16alpha-hydroxy-estrone ratio in premenopausal and postmenopausal women. Epidemiology. 2000 Nov;11(6):635-40.

40. Ho GH, Luo XW, Ji CY, Foo SC, Ng EH. Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk. Ann Acad Med Singapore. 1998 Mar;27(2):294-9.

41. Meng Q, Yuan F, Goldberg ID et al. Indole-3-carbinol is a negative regulator of estrogen receptor-alpha signaling in human tumor cells. J Nutr. 2000 Dec;130(12):2927-31.

42. Muti P, Westerlind K, Wu T, et al. Urinary estrogen metabolites and prostate cancer: a case-control study in the United States. Cancer Causes Control. 2002 Dec;13(10):947-55.

43. Michnovicz JJ, Adlercreutz H, Bradlow HL. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol treatment in humans. J Natl Cancer Inst. 1997 May 21;89(10):718-23.

44. Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. Int J Obes Relat Metab Disord. 1998 Mar;22(3):227-9.

45. Michnovicz JJ, Bradlow HL. Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol. Nutr Cancer. 1991;16(1):59-66.

46. Kall MA, Vang O, Clausen J. Effects of dietary broccoli on human drug metabolising activity. Cancer Lett. 1997 Mar 19;114(1-2):169-70.

47. Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. 2-hydroxyestrone: the ‘good’ estrogen. J Endocrinol. 1996 Sep;150 SupplS259-65.

48. Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: effect of 3,3’-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer. 2004;50(2):161-7.

49. Kristal AR, Lampe JW. Brassica vegetables and prostate cancer risk: a review of the epidemiological evidence. Nutr Cancer. 2002;42(1):1-9.

50. Wong GY, Bradlow L, Sepkovic D, et al. Dose-ranging study of indole-3-carbinol for breast cancer prevention. J Cell Biochem Suppl. 1997;28-29:111-6.

51. Fowke JH, Longcope C, Hebert JR. Brassica vegetable consumption shifts estrogen metabolism in healthy postmenopausal women. Cancer Epidemiol.Biomarkers Prev. 2000 Aug;9(8):773-9.

52. Yoo HJ, Sepkovic DW, Bradlow HL, Yu GP, Sirilian HV, Schantz SP. Estrogen metabolism as a risk factor for head and neck cancer. Otolaryngol Head Neck Surg. 2001 Mar;124(3):241-7.

53. Jin L, Qi M, Chen DZ, et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res. 1999 Aug 15;59(16):3991-7.

54. Sepkovic DW, Bradlow HL, Bell M. Quantitative determination of 3,3’-diindolylmethane in urine of individuals receiving indole-3-carbinol. Nutr Cancer. 2001;41(1-2):57-63.

55. Available at: http://www.cancer.org/docroot/CRI/content/ CRI_2_4_2X_What_are_the_risk_factors_for_breast_cancer_5.asp?rnav=cri. Accessed November 3, 2005.

56. Auborn KJ, Fan S, Rosen EM, et al. Indole-3-carbinol is a negative regulator of estrogen. J Nutr. 2003 Jul;133(7 Suppl):2470S-2475S.

57. Available at: http://clinicaltrials.gov/ct/show/NCT00100958?order=1. Accessed November 3, 2005.

58. Available at: http://clinicaltrials.gov/ct/search?term=dim&diindolylmethane.ID=term&diindolylmethane.badWord=diindolymethane. Accessed November 3, 2005.

59. Rose P, Faulkner K, Williamson G, Mithen R. 7-Methylsulfinylheptyl and 8-methylsulfinyloctyl isothiocyanates from watercress are potent inducers of phase II enzymes. Carcinogenesis. 2000 Nov;21(11):1983-8.

60. Rose P, Huang Q, Ong CN, Whiteman M. Broccoli and watercress suppress matrix metalloproteinase-9 activity and invasiveness of human MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol. 2005 Jun 10.

61. Rose P, Won YK, Ong CN, Whiteman M. Beta-phenylethyl and 8-methylsulphinyloctyl isothiocyanates, constituents of watercress, suppress LPS induced production of nitric oxide and prostaglandin E2 in RAW 264.7 macrophages. Nitric Oxide. 2005 Jun;12(4):237-43.

62. Chiao JW, Wu H, Ramaswamy G, et al. Ingestion of an isothiocyanate metabolite from cruciferous vegetables inhibits growth of human prostate cancer cell xenografts by apoptosis and cell cycle arrest. Carcinogenesis. 2004 Aug;25(8):1403-8.

63. Palaniswamy UR, McAvoy RJ, Bible BB, Stuart JD. Ontogenic variations of ascorbic acid and phenethyl isothiocyanate concentrations in watercress (Nasturtium officinale R.Br.) leaves. J Agric Food Chem. 2003 Aug 27;51(18):5504-9.

64. Hecht SS, Chung FL, Richie JP, Jr, et al. Effects of watercress consumption on metabolism of a tobacco-specific lung carcinogen in smokers. Cancer Epidemiol Biomarkers Prev. 1995 Dec;4(8):877-84.

65. Hecht SS. Chemoprevention by isothio-cyanates. J Cell Biochem Suppl. 1995;22:195-209.

66. Jiao D, Smith TJ, Yang CS, et al. Chemo-preventive activity of thiol conjugates of isothiocyanates for lung tumorigenesis. Carcinogenesis. 1997 Nov;18(11):2143-7.

67. Sticha KR, Kenney PM, Boysen G, et al. Effects of benzyl isothiocyanate and phenethyl isothiocyanate on DNA adduct formation by a mixture of benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mouse lung. Carcinogenesis. 2002 Sep;23(9):1433-9.

68. Tang L, Zhang Y. Dietary isothiocyanates inhibit the growth of human bladder carcinoma cells. J Nutr. 2004 Aug;134(8):2004-10.

69. Zhang Y, Tang L, Gonzalez V. Selected isothiocyanates rapidly induce growth inhibition of cancer cells. Mol Cancer Ther. 2003 Oct;2(10):1045-52.

70. Lhoste EF, Gloux K, De WI, et al. The activities of several detoxication enzymes are differentially induced by juices of garden cress, water cress and mustard in human HepG2 cells. Chem Biol Interact. 2004 Dec 7;150(3):211-9.

71. Pinette KV, Yee YK, Amegadzie BY, Nagpal S. Vitamin D receptor as a drug discovery target. Mini Rev Med Chem. 2003 May;3(3):193-204.

72. Bao BY, Yeh SD, Lee YF. 1{alpha}, 25-dihydroxyvitamin D3 inhibits prostate cancer cell invasion via modulation of selective proteases. Carcinogenesis. 2005 Jun 29.

73. Tangpricha V, Flanagan JN, Whitlatch LW, et al. 25-hydroxyvitamin D-1alpha-hydroxylase in normal and malignant colon tissue. Lancet. 2001 May 26;357(9269):1673-4.

74. Yee YK, Chintalacharuvu SR, Lu J, Nagpal S. Vitamin D receptor modulators for inflammation and cancer. Mini Rev Med Chem. 2005 Aug;5(8):761-78.

75. Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol. 2005 Oct 15.

76. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control. 2005 Mar;16(2):83-95.

77. Danilenko M, Wang Q, Wang X, et al. Carnosic acid potentiates the antioxidant and prodifferentiation effects of 1alpha,25-dihydroxyvitamin D3 in leukemia cells but does not promote elevation of basal levels of intracellular calcium. Cancer Res. 2003 Mar 15;63(6):1325-32.

78. Danilenko M, Studzinski GP. Enhancement by other compounds of the anti-cancer activity of vitamin D(3) and its analogs. Exp Cell Res. 2004 Aug 15;298(2):339-58.

79. Offord EA, Mace K, Avanti O, Pfeifer AM. Mechanisms involved in the chemo-protective effects of rosemary extract studied in human liver and bronchial cells. Cancer Lett. 1997 Mar 19;114(1-2):275-81.

80. Oluwatuyi M, Kaatz GW, Gibbons S. Antibacterial and resistance modifying activity of Rosmarinus officinalis. Phytochemistry. 2004 Dec;65(24):3249-54.

81. Aruoma OI, Spencer JP, Rossi R, et al. An evaluation of the antioxidant and antiviral action of extracts of rosemary and Provencal herbs. Food Chem Toxicol. 1996 May;34(5):449-56.

82. Zhu BT, Loder DP, Cai MX, et al. Dietary administration of an extract from rosemary leaves enhances the liver microsomal metabolism of endogenous estrogens and decreases their uterotropic action in CD-1 mice. Carcinogenesis. 1998 Oct;19(10):1821-7.Chem Toxicol. 1996 May;34(5):449-56.

82. Zhu BT, Loder DP, Cai MX, et al. Dietary administration of an extract from rosemary leaves enhances the liver microsomal metabolism of endogenous estrogens and decreases their uterotropic action in CD-1 mice. Carcinogenesis. 1998 Oct;19(10):1821-7.

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