The safety and efficacy of high-dose chromium - High-Dose Chromium

Alternative Medicine Review, June, 2002 by Davis W. Lamson, Steven M. Plaza

Mutagenic Potential: In vivo Studies

A number of in vivo studies have failed to find any mutagenic potential of Cr III such as was found in the in vitro studies. Rats injected with significant amounts of chromium III chloride were found to have detectable chromium in both kidney and liver chromatin, but 40 hours later were found to have no DNA damage as measured by cross-links or single strand breaks. (65) A recent study looked at the levels of DNA damage from 400 meg/day of chromium as picolinate given to 10 women for eight weeks. Titers of an antibody against an oxidized DNA base (anti-HMdU) showed the supplement dose did not increase oxidative damage to DNA, with a confidence interval of 0.96-1.00. (66) The ability of chromium Ill nitrate to induce a clastogenic reaction at levels of 500 mg/kg by intraperitoneal injection in mice was measured by the micronucleus test. While hexavalent chromium was found to be positive for chromosomal breakage, there was no mutagenic activity of chromium III nitrate. (67)

Glucose Tolerance Factor and Low Molecular Weight Chromium Binding Substance

Although glucose tolerance factor was recognized almost 50 years ago, attempts to isolate the specific structure have eluded scientists to this day. In 1959, Mertz identified trivalent chromium from yeast as the active constituent of GTF, which, when given to brewer's yeast-fed, chromium-deficient rats, corrected imbalances in carbohydrate metabolism. (2) Determination of the biologically active form of chromium focused on the isolation of GTF from brewer's yeast. Acid hydrolysis with 5N HCL for a period of 18 hours was part of the isolation protocol, (68) which would have destroyed most protein structures associated with the bioactive molecule. Yet this protocol led to the discovery of a low molecular weight molecule that was determined to consist of nicotinic acid, glycine, glutamate, and a sulfur-containing amino acid. (69) Although some early studies used porcine kidney as a raw material in the acid hydrolysis isolation procedure, most used readily available yeast as the raw material for GTF studies. (3) Today, the term GTF is reserved for the organic chromium degradation product from yeast. (69) The question as to whether GTF is a biologically active substance or artifact centers on the ability to stimulate production of C[O.sub.2] from glucose in rat adipocytes as a function of insulin concentration. GTF appears to function as a carrier of chromium to the chromium-deficient proteins in the cell. (70)

Analysis of mammalian tissue has resulted in the isolation of a low-molecular-weight chromium binding substance (LMWCr) that in many ways is similar to yeast GTF.

Yamamoto et al (71) isolated two chromium-binding substances: a low molecular weight substance and a high molecular weight substance. The high-molecular-weight chromium binding substance (LMWCr) was isolated from both rabbit liver and mouse organ homogenate and has a molecular weight of 2600 and an ultraviolet absorbance of 260 nm. LMWCr has also been isolated in a number of mammalian organs, including rat lung, (72) rabbit, (73) mouse and canine livers, (71) and from bovine colostrum. (74) LMWCr has a molecular mass of 1500 and has an ultraviolet absorption maximum at 260 nm, which corresponds to the absorption maximum of GTF, also at 260 nm. (69,73) The LMWCr oligopeptide is composed of cysteine, glutamate, aspartate, and glycine. LMWCr differs from GTF in the combination of amino acids and does not contain nicotinic acid. (75) Yet acid hydrolysis of porcine LMWCr, similar to early protocols, yields GTF-like isolates. (57) LMWCr has been found to bind four chromium III ions in a multinuclear assembly much like that of calmodulin. Studies of Vincet et al (57) have discovered that LMWCr is stored in the cytosol of insulin-sensitive cells in an apo (unbound form) that is activated by binding four chromium ions. This activation is the result of a series of steps stimulated by insulin signaling. LMWCr potentiates the action of insulin once insulin has bound to its receptor. (76) (Figure 3)