AHCC

March 2010

Active hexose correlated compound

AHCC

Uses

Most of the medical literature documents the use of AHCC (active hexose correlated compound) as an immunomodulatory agent and its efficacy in therapy for cancer and various infections; however, there is limited information to support the use of this product for any condition.

Dosing

AHCC is primarily available as a capsule. The manufacturer's dosing guidelines recommend two 500 mg capsules by mouth 3 times a day on an empty stomach or 2 capsules by mouth daily for general well-being. A dose of 3 g/day of AHCC in one study led to an increase in specific innate immunity in 4 weeks.

Contraindications

Avoid use if hypersensitive to any of the components of AHCC or to basidiomycete mushrooms.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

A phase I trial reported mild GI complaints, including nausea, diarrhea, and bloating. Some patients also reported headache, fatigue, and foot cramps with the liquid form of AHCC.

Toxicology

A phase I trial documents that AHCC 9 g/day for 14 days had minimal adverse effects and was well tolerated by most patients.

AHCC is an extract prepared from mycelia of several species of basidiomycete mushrooms, including shiitake or Lentinus edodes , after being cultured in a liquid medium. ^1, , ²

AHCC was developed in 1987 at the University of Tokyo Faculty of Pharmaceutical Sciences along with other researchers as a natural product to be used for regulating high blood pressure. However, AHCC is now primarily known for its immune stimulant potential in protecting against viruses, cancers, and infections. ^1, , ²

AHCC is being researched in the United States, China, Korea, Japan, and Thailand. AHCC has been used as a supplement for patients with cancer, AIDS, hepatitis C, diabetes, hypertension, and autoimmune diseases. There are anecdotal claims for its use in treating wounds, stomach ulcers, gum disease, fatigue syndrome, parasites, and multiple sclerosis. ^1, , ³

AHCC contains polysaccharides, amino acids, lipids, and minerals. ^1, , ^2, , ^4, It is obtained by a patented process involving cultivation, enzymatic decomposition, sterilization, concentration, and freeze-drying. ^1, The enzyme-fermented compound is an extract of the mycelia of basidiomycetes mushrooms. Oligosaccharides account for nearly 74% of AHCC, and approximately 20% of these saccharides are partially acetylated alpha-1,4 glucans with a mean molecular weight of 5,000 daltons. ^3, , ^5, The biological activities of AHCC are associated with the acetylated forms of the low molecular weight oligosaccharides. ^2, , ^3, , ⁵

Most of the medical literature documents the use of AHCC as an immunomodulatory agent and its efficacy in cancer and various infections; however, there is limited information to support the use of this product for any condition.

Cancer AHCC is thought to modulate tumor immune surveillance by regulating innate and adaptive immune system responses. The compound may act as a biological response modifier by enhancing natural killer cell activity, interleukin-12 and tumor immunity production, and spleen cell proliferation and cytokine production. ⁶

In vitro and animal data An in vitro study documents how the combination of AHCC plus UFT (tegafur/uracil) enhanced natural killer cell activity in tumor-bearing rats, while UFT treatment alone depressed the natural killer cell activity. In addition, the combination enhanced nitric oxide production and cytotoxicity of peritoneal macrophages. These actions, along with AHCC, restored suppressed mRNA expression of interleukin-1 alpha and tumor necrosis factor (TNF)-alpha induced by the chemotherapy and helped reduce metastasis of rat mammary adenocarcinoma. ⁷

AHCC partially suppressed DNA fragmentation on thymus apoptosis induced by dexamethasone in rats. AHCC may act as an antioxidant to suppress thymic apoptosis or stimulate melatonin secretion that protects thymocytes. ^8, AHCC administration enhanced the serum interleukin-12 level in H-2b mice and is effective in genetically Th1 (or transcription factor T-bet)–dominant mice. Interleukin-12 is considered a critical cytokine for immune system responses in anticancer therapy. ⁹

AHCC may help protect against adverse reactions caused by anticancer drugs. The compound protected against alopecia in rats treated with cytosine arabinoside. Liver injury was significantly reduced in rats treated with mercaptopurine and methotrexate when given AHCC at a dose of 1g/kg simultaneously. ¹⁰

Cisplatin-induced antitumor activity was enhanced with AHCC treatment in mice. AHCC improved the suppression of bone marrow caused by cisplatin, and histopathological examination of the kidney revealed a renal protective effect with AHCC supplementation. ¹¹

Clinical data In patients with malignant tumors, AHCC may increase circulating levels of TNF, interferon gamma, and interleukin 1B. ^8, A 2-week study reported that 3 and 6 g/day of AHCC increased natural killer cell activity in 3 patients with different types of advanced cancer: rhabdomyosarcoma, multiple myeloma, and breast cancer. ^12, The binding capacity of natural killer cells to tumor cells was enhanced 2fold in 17 cancer patients with different advanced malignancies treated with 3 g/day of AHCC by mouth for 2 to 6 months. ^13, A similar 2week study also documented a decline of tumor-associated antigens in 8 of 11 patients treated with AHCC. The mechanism of action was associated with enhanced natural killer cell activity due to an increase of natural killer cell granularity and binding capacity to tumor cell targets. ^14, Compared with baseline, interleukin12, interferon gamma, and natural killer cell activity all increased to normal levels in 38 patients with solid tumors after treatment with AHCC. ¹⁵

AHCC may improve the prognosis of postoperative advanced liver cancer in patients by reducing its recurrence and incidence of death due to the condition or liver cirrhosis. ^16, , ¹⁷

Serologic response improved after treatment with AHCC in a 66yearold patient with castration-resistant prostate cancer, which is an incurable condition with limited treatment options. ¹⁸

One study of 12 different cancer patients reported that AHCC could be used to help prevent bone marrow depression from chemotherapy. ¹⁹

Infection

In vitro and animal data Oral administration of AHCC to food-deprived mice infected with Klebsiella pneumonia promoted clearance of the bacteria and resulted in reduced bacterial load. AHCC also enhanced early immune response by increasing levels of proinflammatory cytokines (ie, interleukin12, TNF-alpha, and interleukin6) and chemokines (MCP-1) that promote clearance and reduction of a variety of pathogens. ⁵ AHCC decreased mortality, increased time to death, and increased clearance of K. pneumonia infection in mice. ^20, , ^21, A similar study in mice discovered that AHCC helped to restore immunity after trauma, infection, and food deprivation. ²²

AHCC increased survival, enhanced natural killer cell activity in the lung and spleen, and rapidly cleared the primary influenza infection or virus from the lungs of infected mice. ^3, The compound works in a dose-dependent manner against acute influenza infection. ²³

AHCC may be useful as a prophylactic drug in managing patients with opportunistic infections. The survival period for mice with cyclophosphamide-induced leukopenia was prolonged after oral or intraperitoneal administration of AHCC at 1,000 or 50 mg/kg/day prior to Candida albicans infection. The kidneys of infected mice also had decreased viable counts of C. albicans . Oral administration of AHCC protected mice from a lethal Pseudomonas aeruginosa infection and intraperitoneal administration protected mice from methicillin-resistant Staphylococcus aureus ^24, , ²⁵ infection.

AHCC administered to aged mice with West Nile encephalitis attenuated viremia levels but did not increase mortality. ²⁶

Clinical data Although the details of the study are lacking, clinical trials in Bangkok reported that HIV patients treated with AHCC have increased or maintained Tcell counts. ²⁷

AHCC at 3 g/day was evaluated for 12 months in 20 HIVpositive men. The results of the study document the following ²⁸ : enhanced natural killer cell activity during the first month, which peaked at the third month and remained consistent during the trial; marked increase in absolute CD4+ cell counts in 14 of 20 patients during the first month and that remained consistent; no change in percentage of the CD4+ cells; increased absolute CD8 cell counts in 12 of 20 patients; and no change in the CD4/CD8 ratio.

Other pharmacologic activity

Antioxidant AHCC ameliorated the strong oxidative effects of ferric nitrilotriacetate in rats. ^29, , ³⁰

Diabetes AHCC prevented cellular damage induced by streptozotocin in rats and protected beta cells from degeneration. ³¹

Inflammatory bowel disease The anti-inflammatory effect of AHCC in rats was comparable with sulfasalazine 200 mg/kg. AHCC administered to rats reduced colonic inflammation, improved body weight, food intake, extension of necrosis, colonic weight, colonic weight-to-length ratio, expression of proinflammatory cytokines and chemokines (IL-1b, IL-1 receptor antagonist, TNF, and monocyte chemoattractant protein-1), and mucosal barrier defense (mucins 2 to 4 and trefoil factor 3). Colonic microflora was also higher in aerobic, lactic acid bacteria, and bifidobacteria counts in rats treated with AHCC, indicating potential use as a prebiotic. ³²

Liver dysfunction Excess nitric oxide production may be involved with liver injury. AHCC may decrease inducible nitric oxide synthase (or iNOS) by reducing mRNA stabilization, rather than inhibiting its synthesis. ^33, , ³⁴

AHCC is primarily available as a capsule. The manufacturer's dosing guidelines suggest administering two 500 mg capsules by mouth 3 times a day on an empty stomach or 2 capsules by mouth daily for general well-being. A dose of 3 g/day of AHCC in one study led to an increase in specific innate immunity in 4 weeks. ³⁵

Information regarding safety and efficacy in pregnancy and lactation is lacking.

AHCC did not inhibit CYP450 activity in one study; however, AHCC is a substrate and inducer of CYP450 2D6. Based on this study, AHCC has the potential for drug-drug interactions involving agents metabolized via CYP450 2D6 (eg, doxorubicin, ondansetron). ³⁶ Adverse drug reactions may potentially occur in patients taking psychiatric medications from the following drug classes: tricyclic antidepressants, selective serotonin reuptake inhibitors, or antipsychotics. Also monitor patients taking pain medications (eg, tramadol) and blood pressure medications, including beta-blockers, for potential adverse reactions.

Historically, the safety profile of AHCC has been well established. A phase I trial documented mild GI complaints, including nausea, diarrhea, and bloating. Some patients reported headache, fatigue, and foot cramps with the liquid form of AHCC. ³⁷

Avoid use with patients who are hypersensitive to any of the components of AHCC or to basidiomycete mushrooms. A phase I trial reported that 9 g/day of AHCC over 14 days resulted in minimal adverse reactions and was well tolerated by most patients. ^37, The median lethal dose of AHCC was 8,490 mg/kg in male rats and 9,849 mg/kg in female rats. Intraperitoneally, the minimal lethal dose of AHCC was lower in the male than in female rats, at 7,430 mg/kg and 8,340 mg/kg, respectively. ¹¹

1. Kenner D. The Japanese Medicinal Mushroom Immune Enhancer: AHCC . Pleasant Grove, UT: Woodland Publishing; 2001.

2. Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev . 2000;5(1):4-27. PubMed

3. Pescatore F, Ritz B. AHCC: a powerful aid in fighting viruses and infections. Total Health Magazine . 2008;30(2):30-31.

4. Ritz BW, Nogusa S, Ackerman EA, Gardner EM. Supplementation with active hexose correlated compound increases the innate immune response of young mice to primary influenza infection. J Nutr . 2006;136(11):2868-2873. PubMed

5. Aviles H, O'Donnell P, Orshal J, Fujii H, Sun B, Sonnenfeld G. Active hexose correlated compound activates immune function to decrease bacterial load in a murine model of intramuscular infection. Am J Surg . 2008;195(4):537-545. PubMed

6. Gao Y, Zhang D, Sun B, Fujii H, Kosuna K, Yin Z. Active hexose correlated compound enhances tumor surveillance through regulating both innate and adaptive immune responses. Cancer Immunol Immunother . 2006;55(10):1258-1266. PubMed

7. Matsushita K, Kuramitsu Y, Ohiro Y, et al. Combination therapy of active hexose correlated compound plus UFT significantly reduces the metastasis of rat mammary adenocarcinoma. Anticancer Drugs . 1998;9(4):343-350. PubMed

8. Burikhanov RB, Wakame K, Igarashi Y, Wang S, Matsuzaki S. Suppressive effect of active hexose correlated compound (AHCC) on thymic apoptosis induced by dexamethasone in the rat. Endocr Regul . 2000;34(4):181-188. PubMed

9. Yagita A, Maruyama S, Wakasugi S, Sukegawa Y. H-2 haplotype-dependent serum IL-12 production in tumor-bearing mice treated with various mycelial extracts. In Vivo . 2002;16(1):49-54. PubMed

10. Sun B, Mukoda T, Kosuna K, Okada F. Reduction of side effects of anticancer drugs by active hexose correlated compound (AHCC) [abstract 92563]. Proc Am Assoc Cancer Res . 1999;40.

11. Hirose A, Sato E, Fujii H, Sun B, Nishioka H, Aruoma OI. The influence of active hexose correlated compound (AHCC) on cisplatin-evoked chemotherapeutic and side effects in tumor-bearing mice. Toxicol Appl Pharmacol . 2007;222(2):152-158. PubMed

12. Ghoneum M, Paul P, Ninomiya Y, Ghonaim M, Gill G. Enhancement of NK cell activity in cancer patients by active hemicellulose compound (AHCC). Paper presented at: Adjuvant Nutrition in Cancer Treatment Symposium; November 67, 1992; Tulsa, OK.

13. Ghoneum M. NK-Immunomodulation by active hemicellulose compound (AHCC) in 17 cancer patients. Paper presented at: 2nd Meeting of the Society for Natural Immunity; May 1994; Taormina, Italy.

14. Ghoneum M, Wimbley M, Salem F, Mcklain A, Attallah N, Gill G. Immunomodulatory and anticancer effects of active hemicelluloses compound (AHCC). Int J Immunotherapy . 1995;X1(1):23-28.

15. Katsuaki U, Kosuna K, Sun B, et al. Active hexose correlated compound (AHCC) improves immunological parameters and performance status of patients with solid tumors. Biotherapy . 2000;14(3):303-309.

16. Matsui Y, Uhara J, Satoi S, et al. Improved prognosis of postoperative hepatocellular carcinoma patients when treated with functional foods: a prospective cohort study. J Hepatol . 2002;37(1):78-86. PubMed

17. Cowawintaweewat S, Manoromana S, Sriplung H, et al. Prognostic improvement of patients with advanced liver cancer after active hexose correlated compound (AHCC) treatment. Asian Pac J Allergy Immunol . 2006;24(1):33-45. PubMed

18. Turner J, Chaudhary U. Dramatic prostate-specific antigen response with activated hemicellulose compound in metastatic castration-resistant prostate cancer. Anticancer Drugs . 2009;20(3):215-216. PubMed

19. Won JS. The hematoimmunologic effect of AHCC for Korean patients with various cancers. Biotherapy . 2002;16(6):560-564.

20. Aviles H, Belay T, Fountain K, Vance M, Sun B, Sonnenfeld G. Active hexose correlated compound enhances resistance to Klebsiella pneumoniae infection in mice in the hindlimb-unloading model of spaceflight conditions. J Appl Physiol . 2003;95(2):491-496. PubMed

21. Aviles H, Belay T, Vance M, Sun B, Sonnenfeld G. Active hexose correlated compound enhances the immune function of mice in the hindlimb-unloading model of spaceflight conditions. J Appl Physiol . 2004;97(4):1437-1444. PubMed

22. Aviles H, O'Donnell P, Sun B, Sonnenfeld G. Active hexose correlated compound (AHCC) enhances resistance to infection in a mouse model of surgical wound infection. Surg Infect (Larchmt) . 2006;7(6):527-535. PubMed

23. Nogusa S, Gerbino J, Ritz BW. Low-dose supplementation with active hexose correlated compound improves the immune response to acute influenza infection in C57BL/6 mice. Nutr Res . 2009;29(2):139-143. PubMed

24. Ishibashi H, Ikeda T, Tansho S, et al. Prophylactic efficacy of a basidiomycetes preparation AHCC against lethal opportunistic infections in mice [in Japanese]. Yakugaku Zasshi . 2000;120(8):715-719. PubMed

25. Ikeda T, Ishibashi H, Fujisaki R, et al. Prophylactic efficacy of a basidiomycetes preparation AHCC against lethal Candida albicans infection in experimental granulocytopenic mice. Nippon Ishinkin Gakkai Zasshi . 2003;44(2):127-131. PubMed

26. Wang S, Welte T, Fang H, et al. Oral administration of active hexose correlated compound enhances host resistance to West Nile encephalitis in mice. J Nutr . 2009;139(3):598-602. PubMed

27. Kenner D. Treatment for immune dysfunction from post-traumatic stress disorder and chronic disease with AHCC. Townsend Letter for Doctors & Patients . 2001;221:68-72.

28. Ghoneum M, Priestly J; International Conference on AIDS. AHCC immunotherapy in AIDS patients. Int Conf AIDS . 1994;10(1):215.

29. Wang S, Ichimura K, Wakame K. Preventive effects of active hexose correlated compound (AHCC) on oxidative stress induced by ferric nitrilotriacetate in the rat. Dokkyo Journal of Medical Sciences . 2001;28(2-3):745-752.

30. Ye SF, Wakame K, Ichimura K, Matsuzaki S. Amelioration by active hexose correlated compound of endocrine disturbances induced by oxidative stress in the rat. Endocr Regul . 2004;38(1):7-13. PubMed

31. Wakame K. Protective effects of active hexose correlated compound (AHCC) on the onset of diabetes induced by streptozotocin in the rat. Biomed Res . 1999;20(3):145-152.

32. Daddaoua A, Martínez-Plata E, López-Posadas R, et al. Active hexose correlated compound acts as a prebiotic and is antiinflammatory in rats with hapten-induced colitis. J Nutr . 2007;137(5):1222-1228. PubMed

33. Matsui K, Kawaguchi Y, Ozaki T, et al. Effect of active hexose correlated compound on the production of nitric oxide in hepatocytes. JPEN J Parenter Enteral Nutr . 2007;31(5):373-380; discussion 380-381. PubMed

34. Matsui K, Ozaki T, Matsumiya M, et al. Active hexose-correlated compound (AHCC) inhibits the induction of iNOS gene expression in proinflammatory cytokine-stimulated hepatocytes. Nitric Oxide . 2008;19:S37.

35. Terakawa N, Matsui Y, Satoi S, et al. Immunological effect of active hexose correlated compound (AHCC) in healthy volunteers: a double-blind, placebo-controlled trial. Nutr Cancer . 2008;60(5):643-651. PubMed

36. Mach CM, Fugii H, Wakame K, Smith J. Evaluation of active hexose correlated compound hepatic metabolism and potential for drug interactions with chemotherapy agents. Soc Integr Oncol . 2008;6(3):105-109.

37. Spierings EL, Fujii H, Sun B, Walshe T. A Phase I study of the safety of the nutritional supplement, active hexose correlated compound, AHCC, in healthy volunteers. J Nutr Sci Vitaminol (Tokyo) . 2007;53(6):536-539. PubMed