# The Double Face of Metals: The Intriguing Case of Chromium
## 2 Chemical Form and Properties of Chromium
Cr(III) is a micronutrient essential in humans for the metabolism of carbohydrates, lipids and proteins. It is considered the main trace mineral involved in the amelioration and prevention of hyperglycemia and hyperlipidemia in T2 DM, as a component of GTF. Administration of Cr(III) orally may markedly alleviate the diabetic-like symptoms [30]. Cr(III) enhances insulin signaling in different tissues [31]. Additionally, trivalent chromium inhibits hepatic enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and interferes with cholesterol metabolism [32]. Cr(III) is also involved in the reduction of plasma cholesterol and triglycerides and in the preservation of normal glucose levels in the blood and in the inhibition of oxidative stress [10]. However, recent studies demonstrated that Cr(III) does not induce human low density lipoprotein (LDL) oxidation at pH 4.5 or 7.4 under the experimental conditions used, thus suggesting caution when evaluating LDL oxidation and lipid peroxidation induced by trivalent chromium [33]. Cr(III) present in the soil may undergo natural oxidation processes being converted to Cr(VI); these oxidation processes may also be influenced by manganese levels. High levels of this metal in the soil as well as the high values of pH in the soil may influence oxidation processes [34]. Trivalent chromium may be easily taken up by plants from the soil; in this way, Cr(III) can enter the food chain of the diet of living beings. Cr(III), as well as being in the daily diet, is present in many nutritional supplements in the form of CrPic, CrHis, CRDC and NBC. Among these nutritional supplements, CrPic is the most easily absorbed [35; 36]. Some in vitro studies evidenced that Cr(III) can react with DNA thus causing DNA damage in cell cultures, but in normal conditions, the limited entry of Cr(III) into cells in vivo limits its genotoxic effects in biological systems. Therefore, the genotoxic effects are rare in animals and humans exposed to nutritional doses or moderate supplemental doses of Cr(III), but they are more likely for modestly elevated physiological intake levels [18]. Cr(VI) is seldom found in nature and it mainly derives from industrial and anthropogenic activities. It is used in industry in stainless steel, chrome plating, welding, leather tanning and as corrosion inhibitor. Cr(VI) is toxic and carcinogenic and is a respiratory irritant which determines phospholipid peroxidation, DNA damage, chromosomal aberration, epigenomic instability and cell death. Cr(VI), which structurally resembles phosphate and sulfate anions, may easily cross cell membranes via nonspecific anionic transfer systems, while Cr(III) cannot enter cells [37]. In the environment Cr(VI) may be found as chromate oxyanion (CrO\({}_{4}\)=), which is structurally similar to sulphate and phosphate anions; for this reason, the anion transport protein, called Band 3, transports sulphate, phosphate and chromate ions, as well [38; 39] (Figure 1). After food or water ingestion, Cr(VI) may be reduced to Cr(III) by the action of saliva and highly acidic gastric juice and then taken by intestinal bacteria [40]. Reduction of Cr(VI) to Cr(III) into cells generates Cr(V) and Cr(IV) intermediate ions: this process depends on the reducing agent and their concentration. Cysteine acts as a one-electron reducer forming Cr(V); the reducing reaction in the presence of GSH proceeds through either one- or two-electron transfer forming Cr(V) and Cr(IV), while ascorbate is a two-electron donor, giving Cr(IV) [37; 41] (Figure 1). Once inside cells, Cr(VI) undergoes metabolic reductions and is converted to Cr(III) in the presence of ascorbate, reduced glutathione (GSH), cysteine (Cys), cytochrome P450 reductase, glutathione reductase, aldehyde oxidase, catalase, glutathione peroxidase, superoxide dismutase, glutathione S-transferase and thioredoxin reductase.