The chromium-binding oligopeptide chromodulin (also known as low-molecular-weight chromium-binding substance) has been shown to activate the tyrosine kinase activity of the insulin receptor in response to insulin and has been proposed to be part of a novel autoamplification mechanism for insulin signaling. The model requires that Cr3+ be moved from the blood to insulin-sensitive tissues in response to insulin and subsequently be lost in the urine as chromodulin; however, the model has not been tested by in vivo studies. In vivo studies with rats have shown that the iron transport protein transferrin serves as the major chromic ion transport agent and that this transport is stimulated by insulin. The ion is transported to a variety of tissues, while liver and kidneys are the major target. In hepatocytes, chromodulin occurs in appreciable levels in the cytosol and in the nucleus. Apochromodulin levels appear to be maintained under homeostatic control, although the only detectable form of urinary chromium is probably chromodulin. Increases in urinary chromium loss in response to insulin are reflected by increases in chromodulin, establishing a direct link between carbohydrate metabolism and the oligopeptide.

The nutritional dietary supplement chromium picolinate, [Cr(pic) 3 ], has gained much notoriety as a safe supplement that supposedly promotes fat loss and muscle enhancement in humans. Thus, a significant industry has materialized around the incorporation of [Cr(pic) 3 ] in many sports foods and drinks and a variety of weight loss products. However, in vitro studies have suggested that low levels of [Cr(pic) 3 ] in the presence of biological reducing agents can catalytically generate reactive oxygen species, and recent in vivo studies have detected oxidative damage in rats receiving the supplement. The potential deleterious in vivo effects of this activity were examined by using Drosophila melanogaster . [Cr(pic) 3 ], but not CrCl 3 , at levels of 260 μg Cr/kg food or less were found to lower the success rate of pupation and eclosion and to arrest development of pupae in a concentration dependent fashion. X-linked lethal analysis indicates that the supplement greatly enhances the rate of appearance of lethal mutations and dominant female sterility.

Chromium picolinate, [Cr(pic)(3)], is the second most popular nutritional supplement after calcium supplements. However, the supplement, unlike simple inorganic Cr(III) salts, has been shown in the presence of biological reducing agents in vitro to catalytically generate appreciable quantities of hydroxyl radicals, resulting in DNA damage. The complex has also been shown to be remarkably stable in vitro at neutral, basic, or weakly acidic pHs. Thus, the significance of this ability to generate hydroxyl radicals depends on whether the complex is absorbed by cells intact along with the stability and concentration of the complex in cells. Consequently, male Sprague Dawley rats have been injected with (51)Cr- and (3)H-labeled [Cr(pic)(3)]. The tissue distribution, urinary and fecal loss, and subcellular hepatocyte distribution and concentration of the labels suggest that [Cr(pic)(3)] has a lifetime of less than 1 day in vivo, minimizing the potential threat from the supplement itself.

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