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Vitamin D Physiology and its Importance in Dairy Cattle: A Review1
Vitamin D Physiology and its Importance in Dairy Cattle: A Review 1 R. C. DOBSON and G. WARD Department of Dairy and Poultry Science. Kansas State University, Manhattan 66506 Abstract
High milk yields make considerable demand on calcium and phosphorus metabolism in the dairy cow. Vitamin D plays a major role in calcium metabolism and, hence, indirectly in phosphorus metabolism. Too often vitamin D has been neglected in current dairy cow nutrition. Several factors including high energy rations, high milk production, and use of exotic rations indicate a need to reevaluate vitamin D nutrition for high producing cows. In rations with sufficient calcium, adebquate vitamin D promotes positive body alance, but natural sources may provide insufficient vitamin D in many highenergy, low-roughage rations. Recent diseoveries of vitamin D metabolites and their role in calcium metabolism have spurred related basic research. Knowledge of vitamin D/calcium metabolism may have practical value in treating and preventing parturient paresis as well as in nutrition per se. In addition, vitamin D may be related to reproductive performanco via enhanced psychic estrus expression. Finally, the knowledge of vitamin D in contemporary dairy cattle nutrition is simply less complete than many believe. Introduction
Discoveries of Steenbock (66) and Hess and Weinstock (34) beganmitigating rickets
as a major medical problem in man and other animals. Their experimental induction of antiraehitie properties to food sterols by ultraviolet irradiation equated these properties with the fat-soluble entity named vitamin D by McCollure et al. (46). Mellanby (47) earlier had produced and subsequently cured or prevented rickets in dogs by feeding cod-liver oil, but he incorrectly ascribed the antiraehitic effect to vitamin A. Received January 14, 1974. a Contribution 887, DailT and Poultry Science Department, KAES, KSU, Manhattan.
Huffman (41) related the knowledge to calves by noting that sunshine counteracted the effects of a rachitic diet. Considerable work in both preventing and producing rickets in calves followed (2, 4, 63). Rickets is rarely a contemporary problem in calves or adult cattle so severe deficiencies are considered briefly. DeLuca (20) de~ned rickets as a condition in which calcification does not keep pace with synthesis of bone organic matrix. Bechtel et al. (4) summarized the generally accepted views on macroscopic and microscopic abnormalities in calf rickets while Craig and Davis (19) commented specifically on dental and oral cavity conditions in rachitie calves. Nearly the sole investigations of acute vitamin D deficiency in mature dairy cows are those of Wallis (70, 71). After being maintained on a vitamin D deficient regimen, cows exhibited lower plasma calcium and phosphorus concentrations (one-half and one-fifth normal, respectively), bone breakage, decreased milk production, and many of the symptoms of rachitie calves. Although Wallis (71) observed bone fragility (osteomalacia) and the failure of all animals to show estrus, he did not relate them directly to vitamin D deficiency. Many others, including Liu et al. (44) and Harrison et al. (30), have established that osteomalacia results from vitamin D deficiency in adult animals. Wallis found feeding cod-liver oil and viosterol remitted symptoms of vitamin D deficiency in cows not yet exhibiting extreme skeletal deformities. After these studies, interest in vitamin D in dairy cattle nutrition waned. Recent advances in vitamin D physiology, possible relationships ot vitamin D to processes heretofore throught unaffected by the vitamin, and stress imposed on high-producing cows make it desirable to review knowledge of vitamin D in dairy-cattle nutrition. Chemistry and Activity of Vitamin D and its Metabolites
Several compounds have different amounts of vitamin D activity. Ultraviolet irradiation of A5,r sterols results in isomerization reaeLions that yield the basic vitamin skeleton (33). Before 1966, six main compounds having calcifying properties had been isolated,
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With an assigned vitamin D activity of 100% for vitamin Dz (cholecalciferol) in the rat and chick, vitamin 1)2 (ergocalciferol) has 100% and 10%, and vitamin D~ has 50 to 75% and 20% activities in the rat and chick, respectively (53, 55). Relative activities of the other vitamin D compounds are even less. What for a time was considered the ultimate functional form of vitamin D, 25-hydroxycholecalcfferol (25-HCC), was isolated from bone, liver, and blood serum (common sites of vitamin D) and characterized by Lund and DeLuca (45). This form is 1.4 times as active as vitamin D in curing rickets (5). Calcium transport in perfused rat intestine has been stimulated by moderate amounts of 25-HCC while larger doses of choleealcfferol had little or no effect (57). Corradino and Wasserman (16) did not confirm entirely Lund and DeLuca's ~ndings. In vitro synthesis of calcium binding protein (CaBP) was increased significantly in their study by including vitamin D3 in the culture medium (0 txg in the control group to 13.5 t~g in the vitamin D3 group). Calcium uptake was increased only about 3.5%. However, they pointed out that the increase was highly reproducible. Dihydrotachysterol-2, a vitamin D: derivative, was nearly as potent as D3 on molar basis. The 25-I-ICC was two to three times more active than D 3 while cholesterol, 7-dehydrocholesterol, ergosterol, hydrocortisone, estradiol, and testosterone were not effective. Of the steroids, only those active in vivo were active in vitro. Only about 1% of vitamin D3 was converted to 25-HCC. They concluded that intestinal mucosa exhibits a relative, rather than an absolute, specificity toward vitamin D-related sterols. Still another metabolite of cholecalcfferol has been isolated from chick intestinal mueosa. Myrtle and Norman (49) named that metabelite 4B and assumed it was the same as the compound designated peak V by Cousins et al. (17, 18) and Gray et al. (27) (same laboratory). Lawson et al. (43) reported a similar compound with faster action and greater potency than for 25-HCC. Norman et al. (56) and Omdahl and DeLuca (60) since have identified that metabolite (4B and peak V) as 1,25-dihydroxycholeealeiferol (1,25-diHCC). Cholecalefferol and 25-HCC both cause maximum calcium transport 24 to 48 h after being administered. Conversely, 1,25-diHCC has a lag time of 9 h and is 13 times as active as eholecaleiferol (49). DeLuea, Kodieek, and Norman (25, 27, 56, 60) indicate that vitamin
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D 3 is converted to 25-HCC in the chick liver, is further hydroxylated to 1,25-diHCC in the kidney, and i~nally is active as 1,25-diHCC in the intestinal mucosa and bone. Rats fed a low phosphorus diet supplemented with 25-HCC synthesized more 1,25-diHCC and had more intestinal calcium transport activity than rats fed the same diet but with adequate phosphorus (68). DeLuca (21) and Wasserman and Corradino (74) have more details on recent discoveries concerning metabolites of vitamin D. General Physiology and Mode of Action
1) Intestinal absorption and excretion. Absorption of ingested vitamin D occurs, with the aid of bile salts, primarily in the lower third of the small intestine. Being lipid soluble, vitamin D enters the lymphatic system and then the blood stream. In the lymphatic system, most of the vitamin is carried in the chylomicron fraction. Excretion of vitamin D is into the feces via bile (33). 2) Blood transport and tissue distribution. After dosage, vitamin D is associated initially with ehylomicrons and lipoproteins in rat blood (62, 65). As time passes, the vitamin increasingly associates with the a~-globulins. That fraction appears to be the main carrier of physiological quantities of vitamin D and 1,25-diHCC. Chen and Lane (11) have shown that it is tightly bound. Vitamin D is typically localized in four organs: liver (as free vitamin D), mucosa of the small intestine, bone, and in the first third of the kidney proximal tubule (7, 42, 52, 53). All those organs except the liver turn over phosphate, citrate, and calcium faster than most other tissues. Conversion to 25-HCC and the resulting association with a2globulins occurs in the liver (40). It seems clear, at least regarding its effects in the intestine, that 25-HCC is converted to 1,25diHCC in the kidney (27); in this form, vitamin D is transferred to the intestine where it is the most active form (27, 43, 49). 3) Action in the intestine and bone. Less contemporary ideas and observation concerning vitamin D's methods of action should not be ignored. Some older studies have meier and others, even though not bio]ogieally basic, may still indicate new approaches. Vitamin D increases calcium absorption and bone turnover. Carlsson e t al. (10) found that serum citric acid decreased slightly, then greatly increased in young rats given vitamin D. Citric acid content of bones and incisors also increased. Fluctuations in serum citric acid were paralleled by
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changes in serum calcium and phosphorus. These workers stated, "The evidence seems to be against the assumption that the effect of vitamin D on citric acid metabolism is secondary to its action on mineral metabolism. By accelerating the production of citric acid in the bones, the solvent action of the vitamin on bone salts is thought to find its explanation." Gaster et al. (26) also reported that rats supplemented with vitamin D had more citric acid per unit of fat free bone. They concluded that vitamin D added to low calcium diets does not increase calcification but increases calcium turnover. Neuman and Neuman (51) suggested that bone crystals and extravascular fluid in contact with bone are not representative of equilibrium. They postulated instead a hydrogen ion gradient between the fluid and the crystals, which fits well with the citratecitric acid observations. Active transport of Ca45 by the intestinal mucosa depends on vitamin D (64). Both absorption and utilization of calcium are increased by vitamin D (8). Coates and Holdsworth (12) noted that calcium absorption was twice as great in chicks supplemented with vitamin Ds as in rachitie controls, but chicks fed a single oral dose of vitamin D and those dosed before hatching did not differ in calcium absorption. Calcium absorption in vitro was enhanced by chick bile. More recent work indicates that 1,25-diHCC is selectively localized in the nucleus of intestinal mueosal cells (31, 32) where it actively facilitates synthesis of CaBP (25, 27, 49). Other reports have linked vitamin D administration less directly with facilitating or stimulating CaBP synthesis and calcium absorption (29). Most likely CaBP synthesis is promoted by 1,25-diHCC influencing the genetie machinery of the cell, but there are unresolved questions. A well-known protein Synthesis inhibitor, actinomycin D, repressed the action of vitamin D on intestinal calcium absorption (54, 75), but that repression was not toxicity per se (76). Hypercaleaemia induced by pharmacological doses of vitamin D is also inhibited by actinomycin D (24), indicating that vitamin D may act on bone as it does in intestinal mueosa. DeLuea and Suttie (22) and Wasserman and Corradino (74) give more detailed information on basic vitamin D physiology. Vitamin D Requirements in Dairy Cattle
In sharp contrast to copious basic work on the mode of action of vitamin D are the few reports on the vitamin D requirements of dairy
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cattle. It is reasonable to assume similar modes of action for vitamin D in the dairy animal, chick, and rat. However, specific peculiarities, i.e., high milk production, skin synthesis, ruminant digestion, and possible estrogenmimicking effects in the dairy cow confound the situation and emphasize the lack of substantial data to establish requirements. Colovos et al. (14) found that vitamin D deficiency seriously impaired calf growth, health, and feed efficiency. Protein digestion, nitrogen retention, and ash digestion were diminished by low vitamin D intake, but digestion of dry matter, ether extract, crude fiber, nitrogen free extract, and energy were not affected. Eff/ciency of both protein and energy decreased. Basic metabolic rate increased, blood calcium, and phosphorus decreased, and blood alkaline phosphatase increased. Rasmussen (61) observed similar growth depression in rats. Re~ardlng manifestations of less severe vitamin D deficiencies, factors other than enhancing positive calcium and phosphorus balances should be examined. The vitamin's relationship to reproduction may prove to be of great practical consideration. Hignett and Hignett (39) observed increased fertility in cattle in good vitamin D status (determined by season rather than supplementation) compared with cattle on lower D intakes. Cohen (13) conducted experiments with 189 anestrus cows. He compared water-soluble crystalline vitamin D3 injections (5 to 10 million IU dose) with no treatment and with subcutaneous gonadotrepin injectiens. More cows exhibited estrus in the D-treated groups (p < .025 compared with no treatanent and p < .05 compared with gonadotropin). Cohen stated that in the observed situations, vitamin DS had estrogenic activity. He also noted that D3 administration terminated broodiness in turkeys (13). Hafez (28) stated that vitamin D indirectly affects female fertility, by affecting calcium and phosphorus utilization. Earlier conception in cows given 300,000 IU supplemental vitamin D weekly was reported by Ward et al. (73). They suggested that vitamin D may alter hormonal concentration and/or expression and thereby account for a higher incidence of observed estrus among supplemented cows. That would account for the shorter average calving interval in cows receiving supplemental D as the improvement apparently-was from detecting otherwise missed estruses rather than from shorter calving-to-first estrus intervals. That is in line with the failure of vitamin D deficient cows to show estrus reported by Wallis JOURNAL OF DAIRY SCIENCI~ VOL. 57, NO. 9
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(71). A precipitous blood-calcium decline occurs in parturient paresis. Attempts to prevent the decline have involved two basic approaches. Some researchers feed low calcium, high phosphorus (6) rations. Hibbs et al. (35, 36, 37) used another approach, that of feeding large amounts of vitamin D. Both methods were expected to stimulate parathyroid activity. Heretofore, parathyroid inadequacy and/or lag in activity were presumed to depress blood calcium at parturition. Lactation and parturition tax the parathyroid (9), but Stott and Smith (67) found no evidence of parhn-ient paresis in cows calving after parathyroidectomy performed immediately prepartum or in midlactation. Hibbs and Pounden (37) fully prevented parturient paresis by feeding 30 million IU of vitamin D daily at least 3 but no more than 7 days prepartum. Normal serum calcium and phosphorus were maintained during the critical prepartum and postpartum periods. Conrad and Hansard (15) investigated the effects of 5 million units of vitamin D given to cows daily for 5 days. Average true digestibility of calcium increased from 48% for the controls to 70% for supplemented cows. Endogenous fecal calcium excretion decreased from 2.27 g per day for controls to 1.64 g per day for vitamin D-supplemented cows. The ealcemie effect of the supplement in cows was not seen in young calves, but older calves retained approximately three times as much calcium with increased Ca 45 deposition in areas of bone growth. Data on vitamin D toxicity in dairy cattle are scarce. Duncan and Huffman (23) produced toxicity in milk fed calves with massive daily doses of viosterol. Hibbs and Pounden (37) reported toxicity in cows fed 30 million IU vitamin D daily for 21 to 30 days. However, cows on the metabolized vitamin D milk program averaged 500,000 IU vitamin D daily with no harmful effects (1). Injections of 25-HCC have been unsuccessful in treating parturient paresis (58); however, as a preventive, 4 mg 25-HCC injected intramuscularly (72 h to 10 days before parturition) significantly reduced the incidence of parturient paresis (59). The greater activity of this compound than cholecalciferol and its lag time, 24 to 48 h for maximum calcium transport, serve to explain its value as a preventive and its failure as a treatment. In an experiment designed to ascertain effect of vitamin D on cows" ability to mobilize JOURNAL OF DAIRY SCIENCE VOL. 57, No, 9
calcium, Muir et al. (48) used ethylenediaminetetraacetate (EDTA) to chelate blood calcium and thus challenge calcium mobilization. With short infusion time, one-half recovery time was the same for vitamin D supplemented and control cows, but cows with a previous history of parturient paresis showed longer one-half recovery times. With more prolonged EDTA infusion, vitamin D-fed cows mobilized calcium one and one-half times Better than controls. It was calculated that two and one-half times the original blood calcium was removed with the infusion, but in the short-time infusion, only one-half of the original calcium was chelated. Vitamin D in the ration is recommended in the following amounts per kilogram of dry matter: 600 IU for calf milk replacer, 250 IU for calf starters, and 300 IU for milking cow rations, yet no vitamin D requirement is listed for animals weighing more than 200 kg (50). Sources used in compiling those recommendations are sketchy at best for calves (3, 14, 63, 69) and even less substantial for mature cows (38, 71). Hibbs and Conrad (38), who fed 32,000 IU vitamin D per pound of concentrate, noticed no ill effects and slightly higher calcium retention in cows having positive phosphorus balances. Par~rient paresis decreased in cows with a history of the disorder after feeding vitamin D. It may be undesirable to feed vitamin D at that rate to cows with no history of the disease. Wallis (71) dealt essentially with remission of deficiency symptoms. Field practices vary considerably, but some dairymen are supplementing rations with vitamin D. Heretofore many thought natural foodstuffs and skin synthesis furnished sufficient vitamin D for mature dairy cows. That may be, but variability, uncertainty, and lack of knowledge reduce confidence in their adequacy. Ward et al. (72) demonstrated improved utilization of calcium by dairy cows receiving 300,000 IU supplemental vitamin D weekly in addition to that in the natural ration consisting of alfalfa hay and grain. Predictability of calcium balance from milk calcium and calcium and phosphorus intakes was enhanced by vitamin D supplementation as well as attaining positive Ca balance early in lactation in cows consuming adequate Ca. Those results support addition of vitamin D to dairy cattle rations as insurance against possible dei~ciency. References
(1) Anonymous. 1961. What about vitamin D toxicity? Mirneo. 6/61. Standard Brands Incorporated, New York.
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( 2 ) Bechdel, S. I., K. G. Landsburg, and O. J. Hill. 1933. Rickets in calves. Pa. Agr. Exp. Sta. Bull. 291. (3) Bochdel, S. I., N. W. Hilston, N. B. Guerrant, and R. A. Duteher. 1938. The vitamin D requirements of dairy calves. Pa. Agr. Exp. Sta. Bull. 364. (4) Bechtel, H. E., E. T. Hallman, C. F. Huffman, and C. W. Duncan. 1936. Pathology of rickets in dairy calves. Mich. Agr. Exp. Sta. Tech. Bull. 364. (5) Blunt, J. W., H. F. DeLuca, and H. K. Sehoes. 1968. The biological activity of 25hydroxycholocalciferol, a metabolite of vitamin I~. Prec. Nat. Acad. SCI. U.S. 61:1503 and Biochemistry 7:3317. (6) Boda, J. M., and H. H. Cole. 1954. The influence of calcium and phosphorus on the incidence of milk fever in dairy cattle. J. Dairy Sci. 37:360. (7) Bosmann, H. B., and P. S. Chen. 1965. Distribution of vitamin D~-4-a~C in rachitic and vitamin Ds treated chicks. Prec. See. Exp. Biol. Med. 120:30. ( 8 ) Campbell, I. L. 1942. Vitamin D, the parathyroid glands, and calcium metabolism. J. Dairy Sci. 25:708. (9) Campbell, I. B., and C. W. Turner. 1950. The relationship of endocrine system to the regulation of calcium metabolism. Me. Agr. Exp. Sta. Bull. 352. (10) Carlsson, A., G. Hollunger, M. Lundquist, and T. Magusson. 1954. Effect of vitamin D on the citric acid metabolism. Aeta. Physiol. Scand. 31:317. (11) Chen, P. S., and K. Lane. 1965. Serum prorein binding of vitamin D3. Arch. Biochem. Biophys. 112:70. (12) Coates, M. W., and E. S. Holdsworth. 1961. Vitamin D. and the absorption of calcium in the chick. Brit. ]. Nutr. 15:131. (13) Cohen, P. H. 1962. Vitamin Ds and the steriod hormones. Vet. Bee. 74:399. (14) Colovos, N. F., H. A. Keener, A. E. Teeri, and H. A. Davis. 1951. The effect of vitamin D on the utilization of energy and prorein of the ration of calves. J. Dairy Sei. 34:735. (15) Conrad, H. R., and S. L. Hansard. 1957. Effects of massive doses of vitamin D on physiology of calcium in cattle. J. AppI. Physiol. 10:98. (16) Corradlno, R. A., and R. H. Wasserman. 1971. Vitamin I~: Induction of calciumbinding protein in embryonic chick intestine in vitro. Science 172:731. (17) Cousins, R..~., H. F. DeLuea, T. Suda, T. ,Chen, and Y. Tanaka. 1970. Metabolism and subcollular location of 25-HCC in intestinal mucosa. Biochemistry 9:1453. (18) Cousins, R. J., H. 17. DeLuea, and R. W. Gray. 1970. Metabolism of 25-HCC in target and nontarget tissues. Biochemistry 9: 3649.
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(19) Craig, J. F., and G. O. Davis. 1943. Rickets in calves. J. Comp. Path. 53:196. (20) DeLuca, H. F. 1967. Mechanism of action and metabolic fate of vitamin D. Vitamin Honn. 25:315. (21) DeLuea, H. F. 1972. Metabolites of vitamin D: New tools of medicine and nutrition. Prec. Cornell Nutr. Conf. 1972. (22) DeLuca, H. F., and J. W. Suttie. 1970. The fat soluble vitamins. University of Wisconsin Press. Madison. (23) Duncan, C. W., and C. F. Huffman. 1934. The effect of daily massive doses of viosterol upon calcium and phosphorus metabolism and blood calcium and inorganic phosphorus in calves. J. Dairy Sci. 17:83. (24) Eisenstein, R., and V. Passavoy. 1964. Ac,tinomyein D inhibits parathyroid hormone and vitamin D activity. Prec. See. Exp. Biol. Med. 177:77. (25) Fraser, D. R., and E. Kodicek. 1970. Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature 228:764. (26) Gaster, D., E. Havivi, and K. Guggenheim. 1967. Interrelationship of calcium, fluorine and vitamin D in bone metabolism. Brit. J. Nutr. 21:413. (27) Gray, B., I. Boyle, and H. F. DeLuca. 1971. Vitamin D metabolism: the role of kidney tissue. Science 172:1232. (28) Hafez, E. S. E. 1959. Reproductive capacity of farm animals in relation to climate and nutrition. J. Amer. Vet. Med. Ass. 135:606. (29) Harmeyer, J., and H. F. DeLuca. 1969. Calcium-binding protein and calcium absorption after vitamin D administration. Arch. Biochem. Biophys. 133:247. (30) Harrison, H. C., H. E. Harrison, and E. A. Park. 1957. Vitamin D and citrate metabolism: Inhibition of vitamin D effect by cortisol. Prec. See. Exp. Biol. Med. 96:768. (31) Haussler, M. R., and A. W. Norman. 1967. tThe subcellular distribution of physiological doses of vitamin I)3. Arch. Biochem. and Biophys. 118:145. (32) Haussler, M. R., J. F. Myrtle, and A. W. Norman. 1968. The association of a metabelite of vitamin Ds with intestinal mucosa chromatin in vivo. J. Biol. Chem. 243:4055. (33) Heftman, E. 1970. Steroid biochemistry. Academic Press. New York. (34) Hess, A. F., and M. Weinstoek. 1924, Antirachitie properties imparted to inert fluids and green vegetables by ukra-viblet irradiation. J. Biol. Chem. 62:301. (35) Hibbs, J. W., W. E. Drams, W. D. Potmden, C. F. Monroe, and T. S. Sutton. 1946. Studies on milk fever in dairy cows. II. The effect of vitamin D on some of the blood changes in normal and milk fever cows at parturition. J. Dairy Sci. 29:767. (36) Hibbs, J. W., W. D. Potmden, and W. Dranss. 1947. Further studies on the effect of vitamin D and of parathyroid extract, JOURNAL OF DAIRY SCII~NCB VOL. 571 NO. 9
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tion on calcium and phosphorus ba/anees. J. Dairy Sci. 55:768. Ward, G., G. B. Marion, C. W. Campbell, and J. R. Dunham. 1971. Influences of calcium intake and vitamin D supplementation on reproductive performances of dairy cows. J. Dairy Sci. 54:204. Wasserman, R. H., and R. A. Corradino. 1971. Metabolic role of vitamins A and D. Ann. Rev. Biochem. 40:501. Zull, J. E., E. Czarnowska-Misztal, and H. F. DeLuca. 1965. Aetinomycin D inhibition of vitamin D action. Science, N.Y. 149:182. ZUll, J. E., E. Czarnowska-Misztal, and H. F. DeLuca. 1966. On the relationship between vitamin D action and aetinomycin sensitive processes. Proc. Nat. Acad. Sci. USA 55:177.
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High milk yields make considerable demand on calcium and phosphorus metabolism in the dairy cow. Vitamin D plays a major role in calcium metabolism and, hence, indirectly in phosphorus metabolism. Too often vitamin D has been neglected in current dairy cow nutrition. Several factors including high energy rations, high milk production, and use of exotic rations indicate a need to reevaluate vitamin D nutrition for high producing cows. In rations with sufficient calcium, adebquate vitamin D promotes positive body alance, but natural sources may provide insufficient vitamin D in many highenergy, low-roughage rations. Recent diseoveries of vitamin D metabolites and their role in calcium metabolism have spurred related basic research. Knowledge of vitamin D/calcium metabolism may have practical value in treating and preventing parturient paresis as well as in nutrition per se. In addition, vitamin D may be related to reproductive performanco via enhanced psychic estrus expression. Finally, the knowledge of vitamin D in contemporary dairy cattle nutrition is simply less complete than many believe. Introduction
Discoveries of Steenbock (66) and Hess and Weinstock (34) beganmitigating rickets
as a major medical problem in man and other animals. Their experimental induction of antiraehitie properties to food sterols by ultraviolet irradiation equated these properties with the fat-soluble entity named vitamin D by McCollure et al. (46). Mellanby (47) earlier had produced and subsequently cured or prevented rickets in dogs by feeding cod-liver oil, but he incorrectly ascribed the antiraehitic effect to vitamin A. Received January 14, 1974. a Contribution 887, DailT and Poultry Science Department, KAES, KSU, Manhattan.
Huffman (41) related the knowledge to calves by noting that sunshine counteracted the effects of a rachitic diet. Considerable work in both preventing and producing rickets in calves followed (2, 4, 63). Rickets is rarely a contemporary problem in calves or adult cattle so severe deficiencies are considered briefly. DeLuca (20) de~ned rickets as a condition in which calcification does not keep pace with synthesis of bone organic matrix. Bechtel et al. (4) summarized the generally accepted views on macroscopic and microscopic abnormalities in calf rickets while Craig and Davis (19) commented specifically on dental and oral cavity conditions in rachitie calves. Nearly the sole investigations of acute vitamin D deficiency in mature dairy cows are those of Wallis (70, 71). After being maintained on a vitamin D deficient regimen, cows exhibited lower plasma calcium and phosphorus concentrations (one-half and one-fifth normal, respectively), bone breakage, decreased milk production, and many of the symptoms of rachitie calves. Although Wallis (71) observed bone fragility (osteomalacia) and the failure of all animals to show estrus, he did not relate them directly to vitamin D deficiency. Many others, including Liu et al. (44) and Harrison et al. (30), have established that osteomalacia results from vitamin D deficiency in adult animals. Wallis found feeding cod-liver oil and viosterol remitted symptoms of vitamin D deficiency in cows not yet exhibiting extreme skeletal deformities. After these studies, interest in vitamin D in dairy cattle nutrition waned. Recent advances in vitamin D physiology, possible relationships ot vitamin D to processes heretofore throught unaffected by the vitamin, and stress imposed on high-producing cows make it desirable to review knowledge of vitamin D in dairy-cattle nutrition. Chemistry and Activity of Vitamin D and its Metabolites
Several compounds have different amounts of vitamin D activity. Ultraviolet irradiation of A5,r sterols results in isomerization reaeLions that yield the basic vitamin skeleton (33). Before 1966, six main compounds having calcifying properties had been isolated,
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With an assigned vitamin D activity of 100% for vitamin Dz (cholecalciferol) in the rat and chick, vitamin 1)2 (ergocalciferol) has 100% and 10%, and vitamin D~ has 50 to 75% and 20% activities in the rat and chick, respectively (53, 55). Relative activities of the other vitamin D compounds are even less. What for a time was considered the ultimate functional form of vitamin D, 25-hydroxycholecalcfferol (25-HCC), was isolated from bone, liver, and blood serum (common sites of vitamin D) and characterized by Lund and DeLuca (45). This form is 1.4 times as active as vitamin D in curing rickets (5). Calcium transport in perfused rat intestine has been stimulated by moderate amounts of 25-HCC while larger doses of choleealcfferol had little or no effect (57). Corradino and Wasserman (16) did not confirm entirely Lund and DeLuca's ~ndings. In vitro synthesis of calcium binding protein (CaBP) was increased significantly in their study by including vitamin D3 in the culture medium (0 txg in the control group to 13.5 t~g in the vitamin D3 group). Calcium uptake was increased only about 3.5%. However, they pointed out that the increase was highly reproducible. Dihydrotachysterol-2, a vitamin D: derivative, was nearly as potent as D3 on molar basis. The 25-I-ICC was two to three times more active than D 3 while cholesterol, 7-dehydrocholesterol, ergosterol, hydrocortisone, estradiol, and testosterone were not effective. Of the steroids, only those active in vivo were active in vitro. Only about 1% of vitamin D3 was converted to 25-HCC. They concluded that intestinal mucosa exhibits a relative, rather than an absolute, specificity toward vitamin D-related sterols. Still another metabolite of cholecalcfferol has been isolated from chick intestinal mueosa. Myrtle and Norman (49) named that metabelite 4B and assumed it was the same as the compound designated peak V by Cousins et al. (17, 18) and Gray et al. (27) (same laboratory). Lawson et al. (43) reported a similar compound with faster action and greater potency than for 25-HCC. Norman et al. (56) and Omdahl and DeLuca (60) since have identified that metabolite (4B and peak V) as 1,25-dihydroxycholeealeiferol (1,25-diHCC). Cholecalefferol and 25-HCC both cause maximum calcium transport 24 to 48 h after being administered. Conversely, 1,25-diHCC has a lag time of 9 h and is 13 times as active as eholecaleiferol (49). DeLuea, Kodieek, and Norman (25, 27, 56, 60) indicate that vitamin
JOURNAL OF DAIRY SCIENCE VOL. 57, NO. 9
D 3 is converted to 25-HCC in the chick liver, is further hydroxylated to 1,25-diHCC in the kidney, and i~nally is active as 1,25-diHCC in the intestinal mucosa and bone. Rats fed a low phosphorus diet supplemented with 25-HCC synthesized more 1,25-diHCC and had more intestinal calcium transport activity than rats fed the same diet but with adequate phosphorus (68). DeLuca (21) and Wasserman and Corradino (74) have more details on recent discoveries concerning metabolites of vitamin D. General Physiology and Mode of Action
1) Intestinal absorption and excretion. Absorption of ingested vitamin D occurs, with the aid of bile salts, primarily in the lower third of the small intestine. Being lipid soluble, vitamin D enters the lymphatic system and then the blood stream. In the lymphatic system, most of the vitamin is carried in the chylomicron fraction. Excretion of vitamin D is into the feces via bile (33). 2) Blood transport and tissue distribution. After dosage, vitamin D is associated initially with ehylomicrons and lipoproteins in rat blood (62, 65). As time passes, the vitamin increasingly associates with the a~-globulins. That fraction appears to be the main carrier of physiological quantities of vitamin D and 1,25-diHCC. Chen and Lane (11) have shown that it is tightly bound. Vitamin D is typically localized in four organs: liver (as free vitamin D), mucosa of the small intestine, bone, and in the first third of the kidney proximal tubule (7, 42, 52, 53). All those organs except the liver turn over phosphate, citrate, and calcium faster than most other tissues. Conversion to 25-HCC and the resulting association with a2globulins occurs in the liver (40). It seems clear, at least regarding its effects in the intestine, that 25-HCC is converted to 1,25diHCC in the kidney (27); in this form, vitamin D is transferred to the intestine where it is the most active form (27, 43, 49). 3) Action in the intestine and bone. Less contemporary ideas and observation concerning vitamin D's methods of action should not be ignored. Some older studies have meier and others, even though not bio]ogieally basic, may still indicate new approaches. Vitamin D increases calcium absorption and bone turnover. Carlsson e t al. (10) found that serum citric acid decreased slightly, then greatly increased in young rats given vitamin D. Citric acid content of bones and incisors also increased. Fluctuations in serum citric acid were paralleled by
REVIEW: VITAMIN D
changes in serum calcium and phosphorus. These workers stated, "The evidence seems to be against the assumption that the effect of vitamin D on citric acid metabolism is secondary to its action on mineral metabolism. By accelerating the production of citric acid in the bones, the solvent action of the vitamin on bone salts is thought to find its explanation." Gaster et al. (26) also reported that rats supplemented with vitamin D had more citric acid per unit of fat free bone. They concluded that vitamin D added to low calcium diets does not increase calcification but increases calcium turnover. Neuman and Neuman (51) suggested that bone crystals and extravascular fluid in contact with bone are not representative of equilibrium. They postulated instead a hydrogen ion gradient between the fluid and the crystals, which fits well with the citratecitric acid observations. Active transport of Ca45 by the intestinal mucosa depends on vitamin D (64). Both absorption and utilization of calcium are increased by vitamin D (8). Coates and Holdsworth (12) noted that calcium absorption was twice as great in chicks supplemented with vitamin Ds as in rachitie controls, but chicks fed a single oral dose of vitamin D and those dosed before hatching did not differ in calcium absorption. Calcium absorption in vitro was enhanced by chick bile. More recent work indicates that 1,25-diHCC is selectively localized in the nucleus of intestinal mueosal cells (31, 32) where it actively facilitates synthesis of CaBP (25, 27, 49). Other reports have linked vitamin D administration less directly with facilitating or stimulating CaBP synthesis and calcium absorption (29). Most likely CaBP synthesis is promoted by 1,25-diHCC influencing the genetie machinery of the cell, but there are unresolved questions. A well-known protein Synthesis inhibitor, actinomycin D, repressed the action of vitamin D on intestinal calcium absorption (54, 75), but that repression was not toxicity per se (76). Hypercaleaemia induced by pharmacological doses of vitamin D is also inhibited by actinomycin D (24), indicating that vitamin D may act on bone as it does in intestinal mueosa. DeLuea and Suttie (22) and Wasserman and Corradino (74) give more detailed information on basic vitamin D physiology. Vitamin D Requirements in Dairy Cattle
In sharp contrast to copious basic work on the mode of action of vitamin D are the few reports on the vitamin D requirements of dairy
98~
cattle. It is reasonable to assume similar modes of action for vitamin D in the dairy animal, chick, and rat. However, specific peculiarities, i.e., high milk production, skin synthesis, ruminant digestion, and possible estrogenmimicking effects in the dairy cow confound the situation and emphasize the lack of substantial data to establish requirements. Colovos et al. (14) found that vitamin D deficiency seriously impaired calf growth, health, and feed efficiency. Protein digestion, nitrogen retention, and ash digestion were diminished by low vitamin D intake, but digestion of dry matter, ether extract, crude fiber, nitrogen free extract, and energy were not affected. Eff/ciency of both protein and energy decreased. Basic metabolic rate increased, blood calcium, and phosphorus decreased, and blood alkaline phosphatase increased. Rasmussen (61) observed similar growth depression in rats. Re~ardlng manifestations of less severe vitamin D deficiencies, factors other than enhancing positive calcium and phosphorus balances should be examined. The vitamin's relationship to reproduction may prove to be of great practical consideration. Hignett and Hignett (39) observed increased fertility in cattle in good vitamin D status (determined by season rather than supplementation) compared with cattle on lower D intakes. Cohen (13) conducted experiments with 189 anestrus cows. He compared water-soluble crystalline vitamin D3 injections (5 to 10 million IU dose) with no treatment and with subcutaneous gonadotrepin injectiens. More cows exhibited estrus in the D-treated groups (p < .025 compared with no treatanent and p < .05 compared with gonadotropin). Cohen stated that in the observed situations, vitamin DS had estrogenic activity. He also noted that D3 administration terminated broodiness in turkeys (13). Hafez (28) stated that vitamin D indirectly affects female fertility, by affecting calcium and phosphorus utilization. Earlier conception in cows given 300,000 IU supplemental vitamin D weekly was reported by Ward et al. (73). They suggested that vitamin D may alter hormonal concentration and/or expression and thereby account for a higher incidence of observed estrus among supplemented cows. That would account for the shorter average calving interval in cows receiving supplemental D as the improvement apparently-was from detecting otherwise missed estruses rather than from shorter calving-to-first estrus intervals. That is in line with the failure of vitamin D deficient cows to show estrus reported by Wallis JOURNAL OF DAIRY SCIENCI~ VOL. 57, NO. 9
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(71). A precipitous blood-calcium decline occurs in parturient paresis. Attempts to prevent the decline have involved two basic approaches. Some researchers feed low calcium, high phosphorus (6) rations. Hibbs et al. (35, 36, 37) used another approach, that of feeding large amounts of vitamin D. Both methods were expected to stimulate parathyroid activity. Heretofore, parathyroid inadequacy and/or lag in activity were presumed to depress blood calcium at parturition. Lactation and parturition tax the parathyroid (9), but Stott and Smith (67) found no evidence of parhn-ient paresis in cows calving after parathyroidectomy performed immediately prepartum or in midlactation. Hibbs and Pounden (37) fully prevented parturient paresis by feeding 30 million IU of vitamin D daily at least 3 but no more than 7 days prepartum. Normal serum calcium and phosphorus were maintained during the critical prepartum and postpartum periods. Conrad and Hansard (15) investigated the effects of 5 million units of vitamin D given to cows daily for 5 days. Average true digestibility of calcium increased from 48% for the controls to 70% for supplemented cows. Endogenous fecal calcium excretion decreased from 2.27 g per day for controls to 1.64 g per day for vitamin D-supplemented cows. The ealcemie effect of the supplement in cows was not seen in young calves, but older calves retained approximately three times as much calcium with increased Ca 45 deposition in areas of bone growth. Data on vitamin D toxicity in dairy cattle are scarce. Duncan and Huffman (23) produced toxicity in milk fed calves with massive daily doses of viosterol. Hibbs and Pounden (37) reported toxicity in cows fed 30 million IU vitamin D daily for 21 to 30 days. However, cows on the metabolized vitamin D milk program averaged 500,000 IU vitamin D daily with no harmful effects (1). Injections of 25-HCC have been unsuccessful in treating parturient paresis (58); however, as a preventive, 4 mg 25-HCC injected intramuscularly (72 h to 10 days before parturition) significantly reduced the incidence of parturient paresis (59). The greater activity of this compound than cholecalciferol and its lag time, 24 to 48 h for maximum calcium transport, serve to explain its value as a preventive and its failure as a treatment. In an experiment designed to ascertain effect of vitamin D on cows" ability to mobilize JOURNAL OF DAIRY SCIENCE VOL. 57, No, 9
calcium, Muir et al. (48) used ethylenediaminetetraacetate (EDTA) to chelate blood calcium and thus challenge calcium mobilization. With short infusion time, one-half recovery time was the same for vitamin D supplemented and control cows, but cows with a previous history of parturient paresis showed longer one-half recovery times. With more prolonged EDTA infusion, vitamin D-fed cows mobilized calcium one and one-half times Better than controls. It was calculated that two and one-half times the original blood calcium was removed with the infusion, but in the short-time infusion, only one-half of the original calcium was chelated. Vitamin D in the ration is recommended in the following amounts per kilogram of dry matter: 600 IU for calf milk replacer, 250 IU for calf starters, and 300 IU for milking cow rations, yet no vitamin D requirement is listed for animals weighing more than 200 kg (50). Sources used in compiling those recommendations are sketchy at best for calves (3, 14, 63, 69) and even less substantial for mature cows (38, 71). Hibbs and Conrad (38), who fed 32,000 IU vitamin D per pound of concentrate, noticed no ill effects and slightly higher calcium retention in cows having positive phosphorus balances. Par~rient paresis decreased in cows with a history of the disorder after feeding vitamin D. It may be undesirable to feed vitamin D at that rate to cows with no history of the disease. Wallis (71) dealt essentially with remission of deficiency symptoms. Field practices vary considerably, but some dairymen are supplementing rations with vitamin D. Heretofore many thought natural foodstuffs and skin synthesis furnished sufficient vitamin D for mature dairy cows. That may be, but variability, uncertainty, and lack of knowledge reduce confidence in their adequacy. Ward et al. (72) demonstrated improved utilization of calcium by dairy cows receiving 300,000 IU supplemental vitamin D weekly in addition to that in the natural ration consisting of alfalfa hay and grain. Predictability of calcium balance from milk calcium and calcium and phosphorus intakes was enhanced by vitamin D supplementation as well as attaining positive Ca balance early in lactation in cows consuming adequate Ca. Those results support addition of vitamin D to dairy cattle rations as insurance against possible dei~ciency. References
(1) Anonymous. 1961. What about vitamin D toxicity? Mirneo. 6/61. Standard Brands Incorporated, New York.
REVIEW: VITAMIN D
( 2 ) Bechdel, S. I., K. G. Landsburg, and O. J. Hill. 1933. Rickets in calves. Pa. Agr. Exp. Sta. Bull. 291. (3) Bochdel, S. I., N. W. Hilston, N. B. Guerrant, and R. A. Duteher. 1938. The vitamin D requirements of dairy calves. Pa. Agr. Exp. Sta. Bull. 364. (4) Bechtel, H. E., E. T. Hallman, C. F. Huffman, and C. W. Duncan. 1936. Pathology of rickets in dairy calves. Mich. Agr. Exp. Sta. Tech. Bull. 364. (5) Blunt, J. W., H. F. DeLuca, and H. K. Sehoes. 1968. The biological activity of 25hydroxycholocalciferol, a metabolite of vitamin I~. Prec. Nat. Acad. SCI. U.S. 61:1503 and Biochemistry 7:3317. (6) Boda, J. M., and H. H. Cole. 1954. The influence of calcium and phosphorus on the incidence of milk fever in dairy cattle. J. Dairy Sci. 37:360. (7) Bosmann, H. B., and P. S. Chen. 1965. Distribution of vitamin D~-4-a~C in rachitic and vitamin Ds treated chicks. Prec. See. Exp. Biol. Med. 120:30. ( 8 ) Campbell, I. L. 1942. Vitamin D, the parathyroid glands, and calcium metabolism. J. Dairy Sci. 25:708. (9) Campbell, I. B., and C. W. Turner. 1950. The relationship of endocrine system to the regulation of calcium metabolism. Me. Agr. Exp. Sta. Bull. 352. (10) Carlsson, A., G. Hollunger, M. Lundquist, and T. Magusson. 1954. Effect of vitamin D on the citric acid metabolism. Aeta. Physiol. Scand. 31:317. (11) Chen, P. S., and K. Lane. 1965. Serum prorein binding of vitamin D3. Arch. Biochem. Biophys. 112:70. (12) Coates, M. W., and E. S. Holdsworth. 1961. Vitamin D. and the absorption of calcium in the chick. Brit. ]. Nutr. 15:131. (13) Cohen, P. H. 1962. Vitamin Ds and the steriod hormones. Vet. Bee. 74:399. (14) Colovos, N. F., H. A. Keener, A. E. Teeri, and H. A. Davis. 1951. The effect of vitamin D on the utilization of energy and prorein of the ration of calves. J. Dairy Sei. 34:735. (15) Conrad, H. R., and S. L. Hansard. 1957. Effects of massive doses of vitamin D on physiology of calcium in cattle. J. AppI. Physiol. 10:98. (16) Corradlno, R. A., and R. H. Wasserman. 1971. Vitamin I~: Induction of calciumbinding protein in embryonic chick intestine in vitro. Science 172:731. (17) Cousins, R..~., H. F. DeLuea, T. Suda, T. ,Chen, and Y. Tanaka. 1970. Metabolism and subcollular location of 25-HCC in intestinal mucosa. Biochemistry 9:1453. (18) Cousins, R. J., H. 17. DeLuea, and R. W. Gray. 1970. Metabolism of 25-HCC in target and nontarget tissues. Biochemistry 9: 3649.
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(19) Craig, J. F., and G. O. Davis. 1943. Rickets in calves. J. Comp. Path. 53:196. (20) DeLuca, H. F. 1967. Mechanism of action and metabolic fate of vitamin D. Vitamin Honn. 25:315. (21) DeLuea, H. F. 1972. Metabolites of vitamin D: New tools of medicine and nutrition. Prec. Cornell Nutr. Conf. 1972. (22) DeLuca, H. F., and J. W. Suttie. 1970. The fat soluble vitamins. University of Wisconsin Press. Madison. (23) Duncan, C. W., and C. F. Huffman. 1934. The effect of daily massive doses of viosterol upon calcium and phosphorus metabolism and blood calcium and inorganic phosphorus in calves. J. Dairy Sci. 17:83. (24) Eisenstein, R., and V. Passavoy. 1964. Ac,tinomyein D inhibits parathyroid hormone and vitamin D activity. Prec. See. Exp. Biol. Med. 177:77. (25) Fraser, D. R., and E. Kodicek. 1970. Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature 228:764. (26) Gaster, D., E. Havivi, and K. Guggenheim. 1967. Interrelationship of calcium, fluorine and vitamin D in bone metabolism. Brit. J. Nutr. 21:413. (27) Gray, B., I. Boyle, and H. F. DeLuca. 1971. Vitamin D metabolism: the role of kidney tissue. Science 172:1232. (28) Hafez, E. S. E. 1959. Reproductive capacity of farm animals in relation to climate and nutrition. J. Amer. Vet. Med. Ass. 135:606. (29) Harmeyer, J., and H. F. DeLuca. 1969. Calcium-binding protein and calcium absorption after vitamin D administration. Arch. Biochem. Biophys. 133:247. (30) Harrison, H. C., H. E. Harrison, and E. A. Park. 1957. Vitamin D and citrate metabolism: Inhibition of vitamin D effect by cortisol. Prec. See. Exp. Biol. Med. 96:768. (31) Haussler, M. R., and A. W. Norman. 1967. tThe subcellular distribution of physiological doses of vitamin I)3. Arch. Biochem. and Biophys. 118:145. (32) Haussler, M. R., J. F. Myrtle, and A. W. Norman. 1968. The association of a metabelite of vitamin Ds with intestinal mucosa chromatin in vivo. J. Biol. Chem. 243:4055. (33) Heftman, E. 1970. Steroid biochemistry. Academic Press. New York. (34) Hess, A. F., and M. Weinstoek. 1924, Antirachitie properties imparted to inert fluids and green vegetables by ukra-viblet irradiation. J. Biol. Chem. 62:301. (35) Hibbs, J. W., W. E. Drams, W. D. Potmden, C. F. Monroe, and T. S. Sutton. 1946. Studies on milk fever in dairy cows. II. The effect of vitamin D on some of the blood changes in normal and milk fever cows at parturition. J. Dairy Sci. 29:767. (36) Hibbs, J. W., W. D. Potmden, and W. Dranss. 1947. Further studies on the effect of vitamin D and of parathyroid extract, JOURNAL OF DAIRY SCII~NCB VOL. 571 NO. 9
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DOBSON AND WARD paroidin, on the blood changes of norma/ and milk fever cows at parturition. J. Dairy Sci. 30:564. Hibbs, J. W., and W. D. Pounden. 1955. Studies on milk fever in dairy cows. IV. Prevention by short-time, preparturn feeding of massive doses of vitamin D. J. Dairy Sci. 38:65. Hibbs, J. W., and H. R. Conrad. 1966. Reevaluation of nutrient allowances for high producing cows. II. Calcium, phosphorus, and vitamin D. ]. Dairy SCI. 49:243. Hignett, S. L., and P. G. Hignett. 1953. The influence of nutrition on reproductive efficiency in cattle. III. The influence of vitamin D status on the effect of calcium and phosphorus intake on the fertility of cows and heifers. Vet. Rec. 65:21. Horsting, M., and H. F. DeLuca. 1969. In vitro production of 25-hydmxycholecalciferol. Bioehem. Biophys. Res. Commun. 36:251. Huffman, C. F. 1931. Make study of rickets in calves. Sunshine counteracts deficiencies in ration that would cause disease. Mich. Agr. Exp. Sta. Quart. Bull. 14:42. Kedicek, E. 1960. The metabolism of vitamin D. Fourth Int. Congr. Biochem. 11:198. Lawson, D. M., P. W. Wilson, and E. Kodicek. 1969. Metabolism of vitamin D: A new choleca/ciferol metabolite, involving loss of hydrogen at C-l, in chick intestinal nuclei. Bioehem. J. 115:269. Liu, S. H., H. I. Chu, C. Su, T. F. Yu, and T. Y. Cheng. 1940. Calcium and phosphorus metabolism in osteomalaeia. IV. Metabolic behavior of infants fed breast milk from mothers showing various degrees of vitamin D nutrition. J. Clin. Invest. 19:327. Lurid, J., and H. F. DeLuca. 1966. Biologically active metabolite of vitamin I)3 from bone, liver and blood serum. J. Lipid Res. 7:739. McCothtm, E. V., N. Sirnonds, J. E. Becker, and P. G. Shipley. 1922. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition. J. Biol. Chem. 53:293. Mellanby, E. 1919. An experimental investigation on rickets. Lancet 196:407. Muir, L. A., J. W. Hibbs, and H. R. Conrad. 1968. Effect of vitamin D on the ability of cows to mobilize blood calcium. J. Dairy Sci. 51:1046. Myrtle, J. F., and A. W. Norman. 1971. Vitamin D: A choleealciferol metabolite highly active in promoting intestinal calcium transport. Science 171:79. National Academy of Sciences-National Research Co~,ncil. 1971. Nutrient requirements of domestic animals. IV. Nutrient requirements of dairy cattle. PubL ISBN 0-309-01916-8.
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(51) Neuman, W. F., and M. W. Neuman. 1958. The chemical dynamics of bone mineral. University of Chicago Press, Chicago, IlI. (52) Neville, P. F., and H. F. DeLuca. 1966. The synthesis of (1,2-sH) vitamin Da and the tissue localization of a 0.25 #g (10 IU) dose per rat. Bioehem. 5:2201. (53) Norman, A. W., J. Lund, and H. F. DeLuca. 1964. Biologically active forms of vitamin I)3 in kidney and intestine. Arch. Bioehem. Biophys. 108:12. (54) Norman, A. W. 1965. Actinomyeln D and the response to vitamin D. Science 149:184. (55) Norman, A. W. 1968. The mode of action of vitamin D. Biol. Rev. 43:97. (56) Norman, A. W., and J. F. Myrtle, R. J. Midgett, and H. G. Nowicki. 1971. 1,25Dihydroxycholecalefferol: Identification of the proposed active form of vitamin D~ in the intestine. Science 173:51. (57) Olson, E. B., and H. F. DeLuca. 1969. 25Hydroxycholecalefferol: Direct effect on calcium transport. Science 165:405. (58) Olson, W. G., N. A. Jorgensen, A. N. Bringe, L. H. Sehultz, and H. F. DeLuea. 1973. 25Hydroxycholecalciferol (25-OHDs) I. Treatment for parturient paresis. J. Dairy Sci. 56:885. (59) Olson, W. G., N. A. Jorgensen, L. H. Schultz, and H. F. DeLnca. 1973. 25-Hydroxycholecalcfferol (25-OHDs) II. Efficacy of parenteral administration in prevention of parturient paresis. J. Dairy Sci. 56:889. (60) Omdahl, J. L., and H. F. DeLnca. 1971. Strontium induced rickets: Metabolic basis. Science 174:949. (61) Rasmussen, P. 1970. The action of vitamin D on the degree of mineralization of bone tissue in rats given adequate amounts of calcium and phosphorus. Brit. J. Nutr. 24: 29. (62) Rikkers, H., and H. F. DeLuea. 1967. An in vivo study of the carrier proteins of ~Hvitamin D3 and D4 in serum. Amer. J. Physiol. 213:380. (63) Rupel, I. W., G. Bohstedt, and E. B. Hart. 1933. Vitamin D in the nutrition of the dairy calf. Wis. Agr. Exp. Sta. Res. Bull. 115. (64) Sehachter, D., and S. M. Rosen. 1959. Active transport of Ca ~ by the small intestine and its dependence on vitamin D. Amer. J. Physiol. 196:357. (65) Sehachter, D., J. D. Finkelstein, and S. Kowarski. 1964. Metabolism of vitamin D. I. Preparation of radioactive vitamin D and its intestinal absorption in the rat. J. Clin. Invest. 43:787. (66) Steenbock, H. 1924. The induction of growth promoting and calcifying properties in a ~ation by exposure to light. Science 60:224. (67) Stott, G. H., and V. R. Smith. 1957. Parturient paresis. VIII. Results of parathyroideetomy of cows. J. Dairy Sci. 40:897. :
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(68) Tanaka, Y., H. Frank, and H. F. DeLuea. 1973. Intestinal calcium transport: Stimulation by low phosphorus diets. Science 181: 564. (69) Thomas, J. W., and L. A. Moore. 1951. Factors affecting the antiraehitic activity of alfalfa and its ability to prevent rickets in young calves. J. Dairy Sci. 34:916. (70) Wallis, G. C. 1938. Some effects of a vitamin D deficiency on mature cows. J. Dairy Sci. 21:315. (71) Wallis, G. C. 1944. Vitamin D deficiency in dairy cows. South Dakota Agr. Exp. Sta. Bull. 372. (72) Ward, G., 1t. C. Dobson, and J. R. Dunham. 1972. Influences of calcium and phosphorus intakes, vitamin D supplement, and lacta-
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