Induction of Chemoprotective Phase 2 Enzymes by Ginseng and its Components

Abstract

Phase 2 detoxification enzymes protect against carcinogenesis and oxidative stress. Ginseng (Panax spp.) extracts and components were assayed for inducer activity of NQO1 (quinone reductase), a phase 2 enzyme, in Hepa1c1c7 cells. Ginseng extracts were analyzed for ginsenosides and panaxytriol. Korean red Panax ginseng extracts demonstrated the most potent phase 2 enzyme induction activity (76 900 U/g dried rhizome powder and 27 800 U/g for two similar preparations). The ginsenoside-enriched HT-1001 American ginseng (Panax quinquefolius) extract was the next most potent inducer, with activity of 15 900 U/g, followed by raw American ginseng root with activity of 8700 U/g. Neither a polysaccharide-enriched extract of American ginseng nor a commercial white Panax ginseng preparation showed any inducer activity. Pure ginsenosides showed no inducer activity. Protopanaxadiol and protopanaxatriol, deglycosylated ginsenoside metabolic derivatives, showed potent induction activity (approximately 500 000 U/g each). Synthetic panaxytriol was over 10-fold more potent (induction potency 5 760 000 U/g). There was no correlation between ginsenoside content and phase 2 enzyme induction. The most potent inducing red ginseng extract also had the highest panaxytriol content, 120.8 µg/g. We found that ginseng induced NQO1 and that polyacetylenes are the most active components.

Key words

antioxidants - anticarcinogenic agents - NQO1 - Panax spp - Araliaceae family - panaxytriol

References

• 1 Gillis C N. Panax ginseng pharmacology: a nitric oxide link?.  Biochem Pharmacol. 1997;  54 1-8
• 2 Attele A S, Wu J A, Yuan C S. Ginseng pharmacology: multiple constituents and multiple actions.  Biochem Pharmacol. 1999;  58 1685-1693
• 3 Yun T K. Panax ginseng – a non-organ-specific cancer preventive?.  Lancet Oncol. 2001;  2 49-55
• 4 Bespalov V G, Alexandrov V A, Limarenko A Y, Voytenkov B O, Okulov V B, Kabulov M K, Peresunko A P, Slepyan L I, Davydov V V. Chemoprevention of mammary, cervix and nervous system carcinogenesis in animals using cultured Panax ginseng drugs and preliminary clinical trials in patients with precancerous lesions of the esophagus and endometrium.  J Korean Med Sci. 2001;  16 (Suppl.) S42-S53
• 5 Yun T K, Choi S Y. Preventive effect of ginseng intake against various human cancers: a case-control study on 1987 pairs.  Cancer Epidemiol Biomarkers Prev. 1995;  4 401-408
• 6 Yun T K, Choi S Y. Non-organ specific cancer prevention of ginseng: a prospective study in Korea.  Int J Epidemiol. 1998;  27 359-364
• 7 Talalay P, Fahey J W. Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism.  J Nutr. 2001;  131 27S-33S
• 8 Talalay P, Dinkova-Kostova A T, Holtzclaw W D. Importance of phase 2 gene regulation in protection against electrophile and reactive oxygen toxicity and carcinogenesis.  Adv Enzyme Regul. 2003;  43 121-134
• 9 Fu Y, Ji L L. Chronic ginseng consumption attenuates age-associated oxidative stress in rats.  J Nutr. 2003;  133 3603-3609
• 10 Maffei Facino R, Carini M, Aldini G, Berti F, Rossoni G. Panax ginseng administration in the rat prevents myocardial ischemia-reperfusion damage induced by hyperbaric oxygen: evidence for an antioxidant intervention.  Planta Med. 1999;  65 614-619
• 11 Kwak M K, Itoh K, Yamamoto M, Kensler T W. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter.  Mol Cell Biol. 2002;  22 2883-2892
• 12 Yun H, Danishefsky S J. Straightforward synthesis of panaxytriol: an active component of red ginseng.  J Org Chem. 2003;  68 4519-4522
• 13 Prochaska H J, Santamaria A B, Talalay P. Rapid detection of inducers of enzymes that protect against carcinogens.  Proc Natl Acad Sci USA. 1992;  89 2394-2398
• 14 Fahey J W, Dinkova-Kostova A T, Stephenson K K, Talalay P. The “Prochaska” microtiter plate bioassay for inducers of NQO1.  Methods Enzymol. 2004;  382 243-258
• 15 Prochaska H J, Santamaria A B. Direct measurement of NAD(P)H : quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers.  Anal Biochem. 1988;  169 328-336
• 16 Fahey J W, Stephenson K K, Dinkova-Kostova A T, Egner P A, Kensler T W, Talalay P. Chlorophyll, chlorophyllin and related tetrapyrroles are significant inducers of mammalian phase 2 cytoprotective genes.  Carcinogenesis. 2005;  26 1247-1255
• 17 Talalay P. Chemoprotection against cancer by induction of phase 2 enzymes.  Biofactors. 2000;  12 5-11
• 18 Helms S. Cancer prevention and therapeutics: Panax ginseng.  Altern Med Rev. 2004;  9 259-274
• 19 Cui J F, Garle M, Bjorkhem I, Eneroth P. Determination of aglycones of ginsenosides in ginseng preparations sold in Sweden and in urine samples from Swedish athletes consuming ginseng.  Scand J Clin Lab Invest. 1996;  56 151-160
• 20 Kim W Y, Kim J M, Han S B, Lee S K, Kim N D, Park M K, Kim C K, Park J H. Steaming of ginseng at high temperature enhances biological activity.  J Nat Prod. 2000;  63 1702-1704
• 21 Wang C Z, Zhang B, Song W X, Wang A, Ni M, Luo X, Aung H H, Xie J T, Tong R, He T C, Yuan C S. Steamed American ginseng berry: ginsenoside analyses and anticancer activities.  J Agric Food Chem. 2006;  54 9936-9942
• 22 Wang C Z, Aung H H, Ni M, Wu J A, Tong R, Wicks S, He T C, Yuan C S. Red American ginseng: ginsenoside constituents and antiproliferative activities of heat-processed Panax quinquefolius roots.  Planta Med. 2007;  73 669-674
• 23 Lee S W, Kim K, Rho M C, Chung M Y, Kim Y H, Lee S, Lee H S, Kim Y K. New polyacetylenes, DGAT inhibitors from the roots of Panax ginseng.  Planta Med. 2004;  70 197-200
• 24 Kim J Y, Lee K W, Kim S H, Wee J J, Kim Y S, Lee H J. Inhibitory effect of tumor cell proliferation and induction of G2/M cell cycle arrest by panaxytriol.  Planta Med. 2002;  68 119-122
• 25 Matsunaga H, Saita T, Nagumo F, Mori M, Katano M. A possible mechanism for the cytotoxicity of a polyacetylenic alcohol, panaxytriol: inhibition of mitochondrial respiration.  Cancer Chemother Pharmacol. 1995;  35 291-296
• 26 Matsunaga H, Katano M, Yamamoto H, Fujito H, Mori M, Takata K. Cytotoxic activity of polyacetylene compounds in Panax ginseng C. A. Meyer.  Chem Pharm Bull (Tokyo). 1990;  38 3480-3482
• 27 Yun H, Chou T C, Dong H, Tian Y, Li Y M, Danishefsky S J. Total synthesis as a resource in drug discovery: the first in vivo evaluation of panaxytriol and its derivatives.  J Org Chem. 2005;  70 10375-10380
• 28 Lee L S, Wise S, Chan C, Flexner C, Lietman P, Flexner C. American ginseng extract reduces oxidative stress markers without altering the pharmacokinetics of zidovudine (abstract accepted). Anaheim, CA; American Society of Clinical Pharmacology and Therapeutics Annual Meeting 2007