National Toxicology Program

Anticarcinogenic Studies. Korean red ginseng and fresh ginseng root have been evaluated in limited studies for anticarcinogenic activity. In mice, prolonged administration of Korean red ginseng (powder dissolved in water at 1 mg per ml) inhibited or prevented carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA), urethane, and aflatoxin B₁. Newborn ICR mice were injected with the carcinogen in the subscapular region within 24 hr of birth. They were subsequently administered Korean red ginseng extract in their water from weaning until they were killed. In the group killed at 48 weeks after DMBA treatment, the average diameter of the largest lung adenomas decreased by 23 percent. In the group killed at 28 weeks after urethane treatment, there was a 22 percent decrease (P<0.05) in the incidence of lung adenoma. In the group killed 56 weeks after aflatoxin B1 treatment, there were decreases in the incidence of lung adenoma (29%) and hepatoma (75%) (P<0.05) (Yun et al., 1983).

Korean red ginseng administered orally (feed, gavage, drinking water; total dose of 17-25 gm) was reported to inhibit liver cancer induced by diethylnitrosamine (DEN) in Wistar rats. Five animals of the experimental and the control group were killed on the 49th day and the 103rd day after the last of 15 doses of DEN had been administered. The remaining seven animals in the experimental group and six animals in the control group were killed on the 161st day. Rats killed before the 161st day had not developed cancer. On the 161st day, one rat given DEN and ginseng developed liver cancer, but all six rats given DEN without ginseng had liver cancer (Wu & Zhu, 1990).

Korean red ginseng, but not fresh ginseng, also inhibited lung adenoma formation in mice. Newborn NIH(G) mice were given suspensions of four-year-old fresh ginseng root (12.9 mg/ml) or Korean red ginseng extract powder (1 mg/ml) dissolved in drinking water ad libitum from date of weaning until they were killed at 9 to 56 weeks. Experimental mice and a positive control group each received a single subscapular injection of urethane, aflatoxin B₁ (AFB), or benzo[a]pyrene (B[a]P) within 24 hours of birth. When red ginseng was given together with urethane, there was a significant reduction in lung adenoma formation observed at 28 weeks (22/30 animals [73%] with adenomas vs. 32/34 [94%]). When red ginseng was given together with AFB, there was also some evidence of a possible chemopreventive effect at 56 weeks (5/29 animals [17%] with adenomas vs. 9/38 [24%]). When red ginseng was given together with B[a]P, a significant anticancer effect was seen (22/80 animals [28%] with adenomas vs. 37/79 [47%]); fresh ginseng was without effect (33/78 animals [42%] with adenomas) (Yun, 1991).

The results of tests for antimutagenic activity of ginseng are limited and somewhat contradictory. Oriental ginseng root, extracted in boiling water, did not demonstrate antimutagenic activity or cytotoxicity in S. typhimurium strains TA98 and TA100; the mutagen was BAP and S-9 was prepared from PCB-induced rats. However, an extract of Panax ginseng increased the rate of DNA excision repair synthesis in V79 cells treated with UV radiation or methyl methanesulfonate. The extract also decreased mutation frequency at the hypoxanthine-guanine phosphoribosyl transferase locus as measured by resistance to 6-thioguanine in V79 cells exposed to methyl methanesulfonate. Components of the ginseng extract also exerted an inhibitory effect on the transformation of NIH 3T3 cells initiated by 3-methylcholanthrene, methyl methanesulfonate, and 1-methyl-3-nitro-1-nitrosoguanidine (Sakai et al., 1988; Rhee et al., 1990).

Studies by Tode and coworkers (1993) on ginsenoside Rh₂ provide some basis for the tumor inhibition observed for red ginseng. These authors noted that Rh₂ caused growth inhibition of cultured B16 melanoma cells and inhibition of the proliferation of cultured human ovarian cancer cells. Extending these studies, the authors demonstrated that intraperitoneal and oral administration of Rh₂ in nude mice caused inhibition of human ovarian cancer cell growth.

Ota and coworkers (1997) summarized other known chemotherapeutic effects of ginsenoside Rh₂ on cancer cells. Crude ginsenosides induced phenotypic reverse transformation in cultured Morris hepatoma cells. Purified ginsenoside Rh₂ inhibited the cell cycle progression at G₁ and/or S phases, stimulated melanogenesis, and induced the expression of an untransformed phenotype in B16 melanoma cells. Rh₂ suppressed the formation of sister chromatid exchanges in human blood lymphocytes. The ginsenosides mixture also enhanced the activity of DNA polymerase d in vitro. These findings suggested to the authors that Rh₂ and related ginsenosides possibly modulate the cellular machinery for the cell cycle progression and/or the cell cycle checkpoint control. To elucidate the molecular mechanisms of the actions by Rh₂, the authors focused on cyclin-dependent kinase-2 (Cdk2), a key kinase in the cell cycle progression during the G1 and S phases. The data clearly revealed that Rh₂ had an inhibitory effect on Cdk2 activity in G₁ arrested cells, but had no inhibitory effect in S arrested cells (Ota et al., 1997).

Other studies indicate that additional ginsenosides may have anticarcinogenic activity. Lee and coworkers (1996) found that Rh₁, as well as Rh₂, was effective at causing differentiation of F9 teratocarcinoma stem cells. Ohtsuka and coworkers (1995) observed that Rb₁ decreased the activity of the direct acting mutagen 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide in S. typhimurium TA100.

CNS Effects. The CNS effects of ginseng are particularly evident when the resistance of the organism is diminished or taxed with extra demands. Thus, ginseng was more effective than placebo in enhancing running performance of young adults, and after taking ginseng radio operators made fewer transmission errors. Experiments with animals also demonstrated the CNS effects of ginseng. For example, rats treated orally with 20 mg ginseng root extract G115 (Ginsana^TM)/ kg for 3 days showed improved performance in behavioral tests designed to assess memory enhancement and retention. Serotonergic transmission or dopaminergic mechanisms have been implicated in ginseng's effects on behavior (Brekhman & Dardymov, 1969; Petkov, 1978; Kim et al., 1992; Gillis, 1997).

Antiviral Effects. A total of 227 volunteers received a 100 mg capsule of Ginsana^TM or placebo for 12 weeks. At week 4, they received an anti-influenza vaccination. By week 12, 42 of the 113 persons in the placebo group and 15 of the 114 persons in the Ginsana^TM group developed influenza or common cold, a highly significant difference (P<0.001). Antibody titers and natural killer activity levels were significantly higher in the Ginsana^TM group by week 8 (Scaglione et al., 1996). Recent studies in normal and athymic rats with pneumonia also showed that animals receiving ginseng treatment for two weeks after infection had significantly reduced bacterial load and less severe lung pathology (Song, 1997).

Diabetes. Administration of ginsenoside-Rb₂ to streptozotocin-induced diabetic rats reduced the level of blood glucose, producing an improvement in hyperglycemia. Rb₂-treated animals also showed a significant decrease in activity of glucose-6-phosphatase, a significant rise of glucokinase activity in the liver, and a moderate increase in glycogen content. Additional studies demonstrated that administration of Rb₂ to diabetic rats stimulated the lipolytic activity of lipoprotein lipase, with a concomitant decrease in the level of triglyceride and very low density lipoprotein in the serum. There was a significant accumulation of lipid in adipose tissue. These data, taken overall, suggested to the authors that ginsenoside Rb₂ may play a role in facilitating the re-esterification of triglyceride fatty acid and glucose in the adipose tissue (Yokozawa et al., 1985).

Cardiovascular Effects. The cardiovascular effects of ginseng root and individual ginsenosides have been studied. Many reports describe vasodilator actions, in some cases followed by vasoconstriction and increase in blood pressure (Gillis, 1997).

Panax notoginseng extracts, injected iv at concentrations >0.5 g/kg, produced marked hypotensive response with bradycardia in albino rats. The hypotensive effect was blocked or reversed by pretreatment with atropine, propanolol, and a combination of chlorpheniramine and cimetidine. Similar results were also observed in rabbits. These results were consistent with the use of Panax notoginseng as an antiangina and antistasis agent in traditional Chinese medicine (Lei & Chiou, 1986).