Ginseng in Skincare and Cancer Prevention: Evidence and commentary T. Jerjian, 2015

Ginseng basics Panax ginseng (ginseng) root has been used medicinally for centuries in many East Asian countries including Korea, Japan, and China. The genus name, Panax, translates to “cure-all” or “all-healing” from Greek, and ginseng is partially derived from the Chinese word for “person,” owing to the root’s distinctive person-like shape.1,2 Ginseng is classified by how the root is prepared; fresh ginseng is grown for less than 4 years and untreated, white ginseng is grown for 4-6 years, peeled and dried, and red ginseng is grown for 6 years, steamed and dried.2 In Korea and China, wild ginseng is believed to be more medicinally potent than farmed.1 Ginseng’s medicinal properties are thought to be attributed to ginsenosides, chemical components that vary with the age and preparation of ginseng. Peak concentrations of ginsenosides are reached around 4-5 years of cultivation, then decline after 6 years. Ginseng root and other parts of the plant contain many chemical constituents other than ginsenosides that may also have medicinal properties.1,3 Ginseng’s myriad of purported benefits include improved immunity, stamina, cognitive function, mood, energy, sexual function, and overall well-being.4 It has been studied for cancer prevention, neurodegenerative diseases, menopausal symptoms, glucose metabolism, and inhibition of melanogenesis among other uses. For the sake of my time and interests (pharmacy, skincare, and cancer), I will be focusing on studies of ginseng for inhibition of melanogenesis and briefly summarize its data for cancer prevention. Also included is pharmacokinetic and safety data.

Note: The pharmacokinetics summarized next are based on oral intake of ginsenosides. I did not find any data related to pharmacokinetics of topical administration, such as with skincare products.

Figure 1: Fresh Panax ginseng roots. (Note the head and leg-shaped parts that contributed to its name).

Pharmacokinetics After oral administration, absorption of ginsenosides is low in the gastrointestinal tract. Gut bacteria transform ginsenosides to active metabolites that are much more readily absorbed and reach peak levels around 10-12 hours after administration.5 Fermentation of ginsenosides results in faster absorption to peak levels, around 3 hours.6 Maximum ginsenoside serum concentrations reached vary among individuals, likely related to variation in gut bacteria.5 Peak serum concentrations reach around one order of magnitude higher with pre-fermented ginsenosides.6 Ginsenosides have been found excreted in urine.7 Drug interaction studies suggest that ginsenosides result in some degree of induction of cytochrome P450 (CYP) 3A4, but this effect seems to be variable, with other studies finding no such action. Ginseng itself does not appear to affect P-glycoprotein (P-gp), but its metabolites may be P-gp substrates.8 There is evidence that intracellular ginsenoside levels are increased by P-gp inhibitors.9 Ginseng may have drug interactions with warfarin resulting in decreased international normalized ratio (INR), phenelzine resulting in headache, tremor, and mania, and alcohol resulting in increased clearance.10

Inhibition of melanogenesis Skin brightening or whitening products are not intended to lighten skin tone, but are used to fade or prevent blemishes and spots from things like postinflammatory hyperpigmentation, acne, and sun damage. Ingredients such as hydroquinone, niacinamide, and arbutin act on melanocytes, the skin cells responsible for the production of melanin. Within melanocytes are melanosomes, the organelles in which melanin is produced. Ginsenosides extracted from ginseng root can also effect the production of melanin similar to the aforementioned ingredients. Ginsenosides are thought to inhibit regulatory enzymes, transcription factors, and signaling pathways of melanin synthesis. They also may induce production of anti-melanogenic compounds and inhibit pro-melanogenic actions. More specifically, ginsenosides directly inhibit tyrosinase in the melanosome. Tyrosinase is a key regulatory enzyme necessary to convert tyrosine to melanin.3

activity of ginseng, as extracts may contain numerous chemical compounds. Though ginsenosides have been implicated, other constituents, such as p-coumaric acid from the leaves, and cinnamic acid from the roots and leaves, have also demonstrated anti-melanogenic acitivity.3 It is important to note that though these effects were prominent in vitro, the skin is a complex organ and absorption and accessibility of topical ginseng to melanocytes will likely be lower. Efficacy of ginseng for burns and atopic dermatitis are in the setting of a damaged barrier, which has altered absorption compared to normal skin.12,13,14 Animal studies of UV damaged skin with less overtly disrupted barrier function did show evidence of ginseng’s efficacy in reverting the damage,15,16 which indicates some degree of absorption into skin is taking place. It is unclear how much, if any, is absorbed systemically from topical absorption. I would like to see in vivo studies similar to those with burns and atopic dermatitis examining ginseng’s effect on melanogenesis, in order to get an idea of the extent of topical absorption and efficacy for this indication. Cancer prevention

Figure 2: Ginseng fruit yield the seeds used for seed extract used in studies of melanogenesis inhibition.

Other components of the ginseng plant, including leaves and seeds, have been shown to inhibit melanogenesis. A recent study of ginseng seed extract showed potent anti-melanogenic activity with less cytotoxicity than root extract. Ginseng seed extract showed about 35% reduction in melanogenesis, greater than that of arbutin (around 27% in this study), another known whitening agent commonly used in “brightening” cosmetics. Ginseng seed extract showed similar but slightly greater tyrosinase inhibition than leaf or root extract, but did not directly inhibit tyrosinase expression, in contrast to the purported mechanism of ginsenosides noted above.11 It is still unclear which compounds specifically are responsible for the antimelanogenic

Epidemiological evidence exists for ginseng’s efficacy in the prevention of occurrence and recurrence of cancer in humans, including lung, liver, ovarian, and various gastrointestinal cancers.1,17 Types of ginseng that showed benefit in these studies included extracts of fresh and white ginseng, any type of red ginseng, and white ginseng powder. These studies revealed approximately 50-60% reductions in cancer incidence and recurrence with time and dose dependent efficacy.18,19 However, they were carried out by the same research group and to my knowledge there have not been any subsequent studies of this type carried out to confirm their findings. In vitro and animal model studies also suggest benefit. Potential anti-cancer mechanisms of action of ginseng include immunomodulation, inhibition of angiogenesis, antioxidant activity, inhibition of proliferation, and induction of apoptosis.1,20 On a related note, there is also evidence of ginseng’s enhancement of chemotherapy or radiation effectiveness in vitro.20

Estrogenicity and other safety considerations Phytoestrogens that resemble human estrogen in structure and function may be present in ginseng extract. Studies have found that ginseng extract is effective at stimulating estrogen receptors in vitro, but results are variable in vivo. One study concluded that the estrogenic activity of ginseng extract is not strong enough to result in physiological response,21 while another found significant estrogenic activity in vivo with varied tissue responses.22 Several case reports have described estrogenic side effects occurring with ginseng use. These effects include breast pain, gynecomastia, and unexplained post-menstrual vaginal bleeding.23,24,25 Notably, one of the reports of vaginal bleeding occurred with use of topical ginseng in face cream, suggesting systemic absorption from topical application.26 Estrogenicity has implications for breast cancer risk and prevention, as discussed in my paraben article. Notably, in the epidemiologic studies described above, ginseng intake was not associated with the prevention of breast or uterine cancers.18 There are still many unknowns in this field, but risks and benefits must always be carefully considered before voluntary use of herbal supplements. Ginseng is generally well tolerated. Other adverse effects include insomnia, diarrhea, nausea, headache, and elevated blood pressure.4,17 A phenomenon formerly known as “ginseng abuse syndrome,”27 which encompassed a culmination of many of ginseng’s side effects occurring after long-term use, has since been debunked, though people may still experience one or many of its adverse effects after short or long-term use.4 Conclusion Ginseng has potential to be an effective active ingredient for brightening skincare, though, as is typical for many herbal supplements and natural medicines, more research is needed to confirm efficacy, and dosing and methods of administration have not been thoroughly explored or standardized. Evidence for ginseng’s prevention of certain types of cancer look promising, but require additional study to confirm efficacy. To optimize use, it would be beneficial to gain a clearer understanding of which chemical components of ginseng are responsible for its various pharmacologic activities, so further research is warranted and may prove valuable.

References 1. Shin HR, Kim JY, Yun TK, Morgan G, Vainio H. The cancer-preventive potential of Panax ginseng: a review of human and experimental evidence. Cancer Causes Control. 2000;11(6):565-76. 2. Yun TK. Brief introduction of Panax ginseng C.A. Meyer. J Korean Med Sci. 2001;16(Suppl):S3-5. 3. Kim K. Effect of ginseng and ginsenosides on melanogenesis and their mechanism of action. J Ginseng Res. 2015;39(1):1-6. 4. Panax ginseng. In: Natural Medicines Comprehensive Database (electronic version). Therapeutic Research Faculty, Stockton, CA, USA. Available at http://www.naturaldatabase.com (cited: 2/13/15). 5. Lee J, Lee E, Kim D, et al. Studies on absorption, distribution, and metabolism of ginseng in humans after oral administration. J Ethnopharmacol. 2009;122(1):143-8. 6. Jin H, Seo JH, Uhm YK, et al. Pharmacokinetic comparison of ginsenoside metabolite IH-901 from fermented and non-fermented ginseng in healthy Korean volunteers. J Ethnopharmacol. 2012;139(2):664-7. 7. Lu JM, Yao Q, Chen C. Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol. 2009;7(3):293-302. 8. Malati CY, Robertson SM, Hunt JD, et al. Influence of Panax ginseng on cytochrome P450 (CYP)3A and P-glycoprotein (P-gp) activity in healthy participants. J Clin Pharmacol. 2012;52(6):932-9. 9. Yang Z, Wang JR, Niu T, et al. Inhibition of Pglycoprotein leads to improved oral bioavailability of Compound K, an anticancer metabolite of red ginseng extract produced by gut microflora. Drug Metabolism and Disposition. 2012;40(8):1538-44. 10. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355(9198):134-8. 11. Lee Y, Kim KT, Kim SS, et al. Inhibitory effects of ginseng seed on melanin biosynthesis. Pharmacogn Mag. 2014:10(Suppl 2):S272-5.

12. Kim HS, Kim DH, Kim BK, et al. Effects of topically applied Korean red ginseng and its genuine constituents on atopic dermatitis-like skin lesions in NC/Nga mice. Int Immunopharmacol. 2011;11(2):280-5. 13. Sohn EH, Jang SA, Lee CH, et al. Effects of Korean red ginseng extract for the treatment of atopic dermatitis-like skin lesions in mice. J Ginseng Res. 2011;35(4):479-86. 14. Kimura Y, Sumiyoshi M, Sakanaka M. Effects of ginsenoside Rb1 on skin changes. J Biomed Biotechnol. 2012;2012:946242. 15. Kang TH, Park HM, Kim YB, et al. Effects of red ginseng extract on UVB irradiation-induced skin aging in hairless mice. J Ethnopharmacol. 2009;123(3):446-51. 16. Lee HJ, Kim JS, Song MS, et al. Photoprotective effect of red ginseng against ultraviolet radiation-induced chronic skin damage in hairless mice. Phytother Res. 2009;23(3):399403. 17. Panax ginseng monograph. Alt Med Rev.2009;14(2):172-6. © Thorne Research, Inc. 18. Yun TK, Choi SY. Preventive effect of ginseng intake against various human cancers: a casecontrol study on 1987 pairs. Cancer Epidemiol Biomarkers Prev. 1995;4(4):401-8. 19. Yun TK, Choi SY. Non-organ specific cancer prevention of ginseng: a prospective study in Korea. Int J Epidemiol. 1998;27(3):359-64. 20. Choi JS, Chun KS, Kundu J, Kundu JK. Biochemical basis of cancer chemoprevention and/or chemotherapy with ginsenosides (Review). Int J Mol Med. 2013;32(6):1227-38. 21. Shim MK, Lee YJ. Estrogen receptor is activated by Korean red ginseng in vitro but not in vivo. J Ginseng Res. 2012;36(2):169-75. 22. Xu Y, Ding J, Ma XP, et al. Treatment with Panax ginseng antagonizes the estrogen decline in ovariectomized mice. Int J Mol Sci. 2014;15(5):7827-40. 23. Palmer BV, Montgomery AC, Monteiro JC. Gin Seng and mastalgia. Br Med J. 1978;1(6122):1284. 24. Kakisaka Y, Ohara T, Tozawa H, et al. Panax ginseng: a newly identified cause of gynecomastia. Tohoku J Exp Med. 2012;228(2):143-5.

25. Greenspan EM. Ginseng and vaginal bleeding. JAMA. 1983;249(15):2018. 26. Hopkins MP, Androff L, Benninghoff AS. Ginseng face cream and unexplained vaginal bleeding. Am J Obstet Gynecol. 1988;159(5):1121-2. 27. Siegel RK. Ginseng abuse syndrome. Problems with the panacea. JAMA. 1979;241(15):1614-5.