Inositol hexaphosphate - Monograph

Alternative Medicine Review, June, 2002

Introduction

Inositol hexaphosphate (IP6), also known as myo-inositol hexaphosphate and phytic acid, is a naturally occurring compound first identified in 1855. IP6 is found in substantial amounts in whole grains, cereals, legumes, nuts, and seeds, and is the primary energy source for the germinating plant. (1,2) IP6 and its lower phosphorylated forms are also found in most mammalian cells, where they assist in regulating a variety of important cellular functions. (2) IP6 functions as an antioxidant by chelating divalent cations such as copper and iron, preventing the generation of reactive oxygen species responsible for cell injury and carcinogenesis. (3) Recently, both in vivo and in vitro studies utilizing IP6 have revealed a significant anticancer activity with a variety of tumor types, possibly via inhibition of tumor cell growth and differentiation. (4) In vitro studies with colon, liver, and rhabdomyosarcoma cell lines, and animal models of mammary, colon, intestinal, and liver cancer, as well as rhabdomyosarcoma, have all demonstrated IP6's anticancer properties. Currently, human clinical trials in cancer are lacking. Other properties of IP6 include an anti-platelet aggregating and lipid-lowering effect, suggesting a potential role in cardiovascular disease; inhibition of HIV-1 virus replication; modulation of insulin secretion in pancreatic beta cells; and inhibition of urinary calcium oxalate crystallization, thereby preventing renal stone development.

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Biochemistry and Pharmacokinetics

Inositol phosphates are synthesized from the parent molecule inositol, with daily dietary consumption of inositol estimated at one gram. Once inositol reaches the cells of the intestinal tract, it is phosphorylated to create inositol hexaphosphate, (5,6) and then subsequently dephosphorylated to its lower forms (IP15), which play important roles in signal transduction) Independent of the route of administration, IP6 has been found to be absorbed almost instantaneously, transported intracellularly and dephosphorylated into lower inositol phosphates. IP6 can reach targeted tumor tissue as early as one hour post-administration. (7) When incubated with a human mammary cancer cell line, low levels of IP6 were detected as early as one minute post-incubation. (8) Pharmacokinetic studies of IP6 in humans are lacking.

Mechanisms of Action

The mechanisms of action for IP6 are not completely understood. A recent study supported earlier research that IP6 functions as an antioxidant by chelating divalent cations such as copper and iron, preventing the formation of reactive oxygen species responsible for cell injury and carcinogenesis. (9) The chelation hypothesis, however, does not completely explain IP6's antineoplastic activity. It is reasonable to conclude that, in addition to its antioxidant role, IP6 probably exerts its action via control of cell division. In a recent study it was shown that IP6 decreased S phase and arrested cells in the G0/G1 phase of the cell cycle. A significant decrease in the expression of proliferation markers indicated IP6 disengaged cells from actively cycling. (10) In addition, IP6 has been shown to enhance NK-cell activity, thereby boosting NK-cell cytotoxicity. (11) Although mechanisms of action pertaining to IP6's anti-platelet aggregating and lipid-lowering effect, its inhibition of HIV-1 replication, and its ability to modulate insulin secretion remain somewhat unclear, it is likely they are a function of IP6's antioxidant properties or its ability to influence a variety of cellular functions. Studies of IP6 and urolithiasis have indicated it inhibits crystallization of calcium oxalate salts in the urine, preventing renal stone development. (12)

Deficiency States

Deficiencies of IP6 have been associated with an increase in calcium oxalate crystals in the urine and resulting increased risk for kidney stone formation. (12) Due to its antioxidant and antineoplastic properties, IP6 deficiency may also pose an increased risk for disease states mediated by reactive oxygen species, such as cardiovascular disease and cancer.

Clinical Indications

Colon Cancer

Epidemiological studies and animal research have suggested an inverse relationship between colon cancer and consumption of high-fiber foods. Among the many components of fiber, inositol hexaphosphate has been studied extensively for its inhibitory effects against colon carcinogenesis. Rat studies have demonstrated IP6 reduces tumor prevalence, frequency, and size in a dose-dependent manner during the initiation and post-initiation stages. (13,14) Another study examining the preventive effects of wheat bran fractions in rat colon cancer showed that removal of both IP6 and lipids from wheat bran significantly increased colon tumor multiplicity and volume. Removal of IP6 or lipids independent of each other had no significant effect on colon tumor incidence, (15) possibly suggesting the two fractions operate together to inhibit carcinogenesis.