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1 Introduction Chromium (Cr) has been considered an essential nutrient for humans and animals for approximately 40 years, and there are excellent reviews that detail several aspects of its function in nutrition (Anderson, 1987, 1988; Borel and Anderson, 1984; Prasad, 1978; Underwood, 1977~. Chromium exists in nature mostly in the trivalent (Cr+3) form. Chromium (Cr+3) has been shown to have antioxidative properties in vivo (Tezuka et al., 1991), and it is integral in activating enzymes and maintaining the stability of proteins and nucleic acids (Borer and Anderson, 1984~. Its primary metabolic role, however, is to potentiate the action of insulin through its presence in an organometallic molecule called the glucose tolerance factor (GTF). Schwarz and Mertz (1957, 1959) first isolated GTF from pork kidney (1957) and brewer's yeast (1959), and it is believed to consist of Cr+3, nicotinic acid, glutamic acid, glycine, and cysteine (Toepfer et al., 1977~. Without Cr+3 at its core, GTF is inactive. Most chromium in animal tissues is present in GTF. In addition to GTF in yeast and animal tissues (Anderson, 1987), bovine colostrum contains at least five low-molecular-weight, chromium-containing sub- stances (Yamamoto et al., 1988~. One has biological activity and is an ionic complex consisting of chromium with aspartate, glutamate, glycine, and cysteine in a molar ratio of 5:4:2:1, and no detectable carbohydrate. A similar and biologi- cally active chromium-containing substance has been found in rabbit liver (Yamamoto et al., 1989~. Although relatively rare, signs of chromium deficiency are likely related to its interactions with insulin, and they include impaired glu- cose tolerance, elevated concentrations of insulin, glycosuria, impaired growth, decreased longevity, elevated concentrations of cholesterol and triacylglycerols, 6
INTRODUCTION increased aortic plaques, brain disorders, decreased fertility, and peripheral neu- ropathy (Borer and Anderson, 1984~. ABSORPTION, TRANSPORT, AND CONTENT IN ANIMAL TISSUES 7 Chromium is absorbed primarily in the small intestine. The most active site of absorption in rats seems to be the jejunum, with less efficient absorption occurring in the ileum and duodenum (Chen et al., 1973~. Inorganic forms, such as that present in chromic chloride (CrCl3 ~ (as heptahydrate) and chromic oxide (Cr2O3), are absorbed poorly. The average absorption of Cr+3 has been estimated at 0.5 percent. The efficiency of absorption, however, is related inversely to dietary intake. Anderson (1987) reported that approximately 2 percent of dietary chromium was absorbed in humans consuming approximately 10,ug/day, whereas absorption efficiency was decreased to 0.5 percent when their intake was >40,ug/ day. Abnormal absorption has been reported in insulin-requiring diabetics. Doisy et al. (1976) reported that insulin-requiring diabetics absorbed two to four times more chromium than was absorbed by normal subjects. The authors hypoth- esized that insulin-requiring diabetics are chromium deficient and develop an adaptive increase in absorption to help offset the deficiency. Almost all sources of chromium in the Earth's crust are in the trivalent state. There are, however, manufactured forms (K2Cr2O7, K2CrO4, and Na2CrO4) that exist in the hexavalent (Cr+6) state. These forms are more soluble than is Cr+3 and, when administered directly into the intestine, are absorbed three to five times better than Cr+3 (Anderson, 1987~. When taken orally, however, most of the Cr+6 is believed to be reduced to Cr+3 before reaching sites of absorption in the small intestine (Doisy et al., 1976~. The reasons for the low availability of inorganic sources of Cr+3 are many and probably are related to formation of insoluble chromic oxide, binding to natural chelating agents in foodstuffs (such as phytate), and interference by ionic forms of other elements (zinc, iron, and vana- dium) (Borer and Anderson, 1984), slow or no conversion of inorganic chromium to the bioactive form (Ranhotra and Gelroth, 1986), and suboptimal amounts of nicotinic acid (Urberg and Gemel, 1987~. The content of total chromium in the diet, therefore, probably bears little relationship to its effectiveness as biologi- cally active chromium. Complexing chromium to organic molecules also can influence availability. For example, oxalate enhanced the absorption of chromium in rats, whereas EDTA and citrate did not (Chen et al., 1973~. Other synthetic organic forms, such as chromium nicotinate (CrNic) and chromium picolinate (CrPic), also have been used as readily available sources of chromium. Olin et al. (1994) reported that absorption of chromium by rats during the first 12 hours after oral adminis- tration was greatest for CrNic and least for CrCl3, with absorption from CrPic ranking intermediate. Anderson et al. (1996b) determined the relative bioavail
8 THE ROLE OF CHROMIUM IN ANIMAL NUTRITION ability of nine different organic and inorganic forms of chromium by measuring the incorporation of chromium into tissues of rats fed these various chromium sources. They demonstrated that chromium incorporation into tissues is highly dependent upon the form, with the greatest incorporation occurring from chro- mium dinicotinic acid diglycine cysteine glutamic acid, CrPic, chromium acetate, chromium potassium sulfate, and glycine chromium complexes. They also con- cluded that chromium chloride was a very poor source of chromium and that raising animals in stainless steel cages did not result in significant changes in tissue chromium concentrations. Naturally occurring chromium complexes also are known for their relatively high biologic availability. Experiments with rats, for example, suggest that 10 to 25 percent of the chromium in brewer's yeast is absorbed (Underwood, 1977~. Good natural sources, in addition to brewer's yeast, include dark chocolate, black pepper, and some processed meats (Hunt and Stoecker, 1996; Toepfer et al., 1973~. Once absorbed, chromium circulates in plasma at a concentration of 0.01- 0.3 ,uglL (Anderson, 1987~. These plasma concentrations are much lower than those reported before 1980, largely because of the increased sensitivity of chro- mium analysis made possible by use of the graphite furnace in conjunction with atomic absorption spectrophotometry (Mertz, 1993b). As described by Mertz (1993b), detection of such low serum concentrations requires strict control of contamination by performing sample preparation and analysis in ultraclean ex- perimental rooms and by constant quality control with the use of standard refer- ence materials. Plasma concentrations of chromium can be lower during infec- tion and glucose loading (Borer and Anderson, 1984~. Circulating chromium is associated with the p-globulin portions of plasma and, in physiologic concentrations, is transported to tissues bound to transferrin and possibly as a component of GTF (Prasad, 1978~. Chromium, therefore, can have significant effects on serum iron transport. Ani and Moshtaghie (1992), for example, demonstrated that intraperitoneal injections of CrCl3 in rats can signifi- cantly decrease serum iron, total iron-binding capacity, and ferritin. At super- physiologic concentrations, chromium binds nonspecifically to other plasma pro- teins (Prasad, 1978~. Plasma is cleared of chromium within a few days of administration (Ander- son, 1987~. Whole-body chromium, however, is cleared in rats at a much slower rate and has been expressed as a three-compartment model with half-lives of 0.5, 6, and 83 days (Borer and Anderson, 1984~. Some tissues, such as bone, testes, and epididymides, retain chromium longer than do the heart, lung, pancreas, or brain. Unlike some other elements (e.g., calcium and magnesium), it seems that no equilibrium exists between tissue stores of chromium and plasma. Concentra- tions in plasma are, therefore, a poor indicator of chromium status. Total body chromium concentrations decrease with age, which is reflected in a decrease in tissue uptake. In pharmacokinetic experiments, older mice had less ability to
INTRODUCTION 9 concentrate chromium in several tissues than did younger animals. The reasons for these differences in tissue uptake are unknown. Absorbed chromium is excreted mainly in the urine. Small amounts, how- ever, are lost in hair, perspiration, and bile. The 24-hour urinary excretion rate for normal human subjects is reported to be 0.22 ,ug/day (Borer and Anderson, 1984), which is consistent with the relatively low absorption rate (approximately 0.5 percent) and typical daily chromium consumption rates (62-85 ,ug/day). Uri- nary excretion of chromium has been shown to increase after oral loading of glucose in healthy patients and is higher in human diabetics (Borer and Anderson, 1984~. Stress and exercise also can result in increased urinary chromium excre- tion. Anderson (1988) reported that, in adult males, a six-mile run resulted in a fivefold increase in urinary chromium excretion within two hours after running, and the total urinary chromium excreted during the day of the run was more than twice that on the next day. Severely traumatized patients also excrete several times more chromium than do normal subjects. Urinary chromium excretion is, therefore, probably not a good indicator of dietary chromium status.
