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Vitamin K Henrik Dam discovered vitamin K as the result of experiments he was carrying out to determine whether cholesterol was a dietary essential. Dam (1929) noted a hemorrhagic syndrome in chicks fed diets that had sterols extracted by lipid solvents. He eventually iso- lated an active antihemorrhagic factor from alfalfa that E. A. Doisy's research group characterized as 2-methyl- 3-phytyl-1,4-napthoquinone (MacCorquodale et al., 19391. Early investigations established that vitamin K deficiency resulted in decreased activity of prothrombin in plasma. As they were discovered, the synthesis of clotting factors VIl, IX, and X was also shown to be vitamin K-dependent. More recently, it has been shown that a number of other proteins, many with presently undetermined functions, require vitamin K for their bio- synthesis. Dam (1964), Almquist (1975), and Suttie (1985a) have reviewed the historical and more recent aspects of vitamin K nutrition and function. NUTRITIONAL ROLE Dietary Requirements of Various Species Dietary adequacy of vitamin K is often defined as the amount of vitamin needed to maintain normal levels of plasma vitamin K-dependent clotting factors. It has been difficult to demonstrate clearly and to measure dietary vitamin K requirements for many species. Pre- sumably this is because of the varying degrees to which different species utilize the large amount of vitamin K synthesized by bacteria in the lower gut and the degree to which they practice coprophagy. A spontaneous defi- ciency of vitamin K was first noted in chicks; poultry are much more likely to develop dietary deficiency signs than any other species. Ruminants do not appear to need a source of vitamin K in the diet because the vita min is synthesized by rumen microorganisms and sequently utilized. Vitamin K deficiencies have been produced in most nonruminant species.~Nevertheless, estimations of requirements made by different workers are difficult to compare because of the use of different forms of the vitamin and different methods to establish dietary requirements. Some investigators have mea- sured the amount of vitamin K needed to cure the clotting defect in vitamin K-deficient hypoprothrombi- nemic animals; others have determined the minimal di- etary concentrations of vitamin needed to prevent ap- pearance of hypoprothrombinemia. Scott (1966), Doisy and Matschiner (1970), and Griminger (1971) have discussed the vitamin K reouire - -A - s~h ments of various species in detail. The requirement for most species ranges from 1 to 10 fig of vitamin K/kg of BW/day (50 to 150 ,Ag/kg of diet) for most nonruminant animals; 50 to 250 ~g/kg of BW/day (0.5 to 1.5 mg/kg of diet) for poultry. A dietary vitamin K requirement in the adult human has been difficult to establish but is usually stated to range from 0.5 to 1.5 lag vitamin K/kg of BW/ day (Olson, 19803. Biochemical Functions In the absence of adequate amounts of vitamin K or in the presence of vitamin K antagonists, animals develop bleeding disorders. These disorders result from an in- ability of a liver microsomal enzyme, now called the vitamin K-dependent carboxylase (Esmon et al., 1975), to carry out the normal post-translational conversion of specific glutamyl residues in the vitamin K-dependent plasma proteins to y-carboxyglutamyl residues (Nelses- tuen et al., 1974; Stenflo et al., 1974~. These residues are essential for the normal Ca+ +-dependent interaction of the vitamin K-dependent clotting factors with phospho- lipid surfaces. The result of insufficient vitamin K to 31

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32 Vitamin Tolerance of Animals serve as a cofactor for this enzyme is, therefore, a de- crease in the rate of thrombin generation. This decrease subsequently results in a decreased rate of fibrin clot formation and an increased susceptibility to hemor- rhage. The molecular role of vitamin K in the enzymatic reaction is understood in a general sense, but a number of details of the chemical mechanisms remain to be clari- fied (Suttie, 1985b). FORMS OF THE VITAMIN Compounds exhibiting vitamin K activity possess a 2- methyl-1,4- napthoquinone ring. The term "vitamin K" is used as a generic descriptor for both 2-methyl-1,4- napthoquinone and all 3-substituted derivatives of this compound, which exhibit an antihemorrhagic activity in animals fed a vitamin K-deficient diet (see Figure 81. The form of the vitamin isolated from plants, 2-methyl- 3-phytyl-1,4-napthoquinone, is generally called vitamin Kit or phylloquinone. The vitamin originally isolated from purified fish meal, which was called vitamin K2, is now known to be only one of a series of bacterially syn- thesized vitamins K with unsaturated polyisoprenoid side chains at the 3-position. These are called mena- quinones (MK). The predominant vitamins of the mena- quinone series contain a side chain of 6 to 10 isoprenoid units (MK-6 through MK-101; however, forms with up to 13 isoprenoid groups have been identified, as well as several forms with partially saturated side chains. The parent compound of the vitamin K series, 2-methyl-1, 4- napthoquinone, is a synthetic product that was once called vitamin K3 but is now more commonly and cor- rectly designated as menadione. Enzymes in mamma ~3 o Menadione Phylloquinone o MK-7 FIGURE 8 Chemical structures of three major forms of vita- min K. o at. 3 lien tissue are capable of alkylating menadione to active forms of the vitamin, and MK-4 appears to be the pre- dominant species formed. A limited number of forms of vitamin K are currently available for therapeutic and nutritional use. Phyllo- quinone (USP phytonadione) is the preferred form of the vitamin for clinical use and is available as a colloidal suspension, an emulsion, and an aqueous suspension for parenteral use, and as a tablet for oral use. Menadione is available as a tablet for oral administration. A water- soluble form of menadione, menadiol sodium diphos- phate, is also available for parenteral use. Vitamin K is widely used by the animal industry, particularly in poul- try feeds. Because of the expense of phylloquinone, var- ious water-soluble forms of menadione are the predominant sources used. Menadione forms a water- soluble sodium bisulfite addition product, menadione sodium bisulfite (MSB). In the presence of excess so- dium bisulfite, MSB crystallizes as a complex with an additional mole of sodium bisulfite to form a compound called menadione sodium bisulfite complex (MSBC). This form has increased dietary stability compared to menadione and MSB and, therefore, is widely used in the poultry industry. A third water-soluble compound is a salt called menadione pyridinol bisulfite (MPB), which is formed by the addition of dimethylpyridinol. These three forms of menadione, and phylloquinone, have roughly equal biological activity on a molar basis in poul- try diets. One of the menadione forms is usually added to the diets of laboratory animals and sometimes to those ~ . 01 swine. ABSORPTION AND METABOLISM Vitamin K is absorbed from the intestine into the lym- phatic system of mammals by a process that requires the presence of both bile salts and pancreatic juice for opti- mal formation of mixed micellar structures. Shearer et al. (1974) have studied the absorption of radioactive phylloquinone. They found that fecal excretion of the unmetabolized form following a 1-mg dose of phyllo- quinone was less than 20 percent in normal subjects but increased to more than 70 percent in patients with im- paired fat absorption. Animal diets could contain mena- dione, a mixture of menaquinones and phylloquinone, and there is evidence that the absorption of these vari- ous forms of vitamin K differs significantly. A series of investigations (Hollander, 1981) has demonstrated that phylloquinone is absorbed from the proximal small in- testine by an energy-requiring process. On the other hand, menaquinone-9 is absorbed from the small intes- tine by a passive, noncarrier-mediated process. Mena

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Vitamin K 33 dione appears to be absorbed from both the colon and the small intestine by passive processes. Suttie (1985a) has recently reviewed the distribution of various forms of vitamin K in tissues and the vita- min's metabolism. Almost 50 percent of a physiological dose of phylloquinone localizes in the liver at 3 hours after parenteral administration, while only 2 percent of a dose of menadiol diphosphate localizes in this tissue by that time. Although phylloquinone is rapidly concen- trated in liver, it has a relatively short biological half-life. After a rapid drop during the first few hours following peak levels, injected phylloquinone has been shown to be removed from rat liver with a half-life of less than a day, suggesting very little long-term storage. Menaa~uinone-4 is the major lipophilic product of mena- dione metabolism formed when low doses of menadione are administered. Menadione is rapidly metabolized, and three different urinary conjugates the phosphate, sulfate, and glucuronide of menadiol have been identified. The major route of excretion of intravenously administered radioactive phylloquinone appears to be fecal, with only a small percentage of fecal radioactivity present as un- metabolized phylloquinone. The metabolism of radioac- tive phylloquinone has now been studied in both the rat and in humans, and the glycones of the 5- and 7-carbon side chain carboxylic acid derivatives appear to be ma- jor excretion products. A significant amount of vitamin K stored in tissue is present as the 2,3-epoxide of the vitamin (Matschiner et al., 1970~. It is likely that epox- ide is also subjected to degraded metabolism before ex- cretion. There are undoubtedly a number of metabolites and excretion products that have not yet been identi- fied. HYPERVITAMINOSIS Early studies of vitamin K supplementation indicated the relative lack of toxic symptoms. Few systematic studies of the effects of excess vitamin administration have been carried out. Molitor and Robinson (1940) made a brief but rather comprehensive study of the tox- icity of menadione and phylloquinone soon after the vi- tamin was discovered. Ansbacher et al. (1942), Smith et al. (1943), and Richards and Shapiro (1945) carried out standard pharmacological studies of menadione or menadione bisulfite in the next few years. These studies utilized standard laboratory animals and are summa- rized in Table 9. From these data it can be concluded that the LD50 for a single parenteral dose of menadione or its water-soluble derivative is in the range of 75 to 200 mg/kg of BW for chicks, mice, rats, rabbits, and dogs, and the LD~n for a single oral dose is 600 to 800 mg/kg of - - - ~} v ~ -- -O - ~ BW at least for chicks and mice. These dosage levels are several orders of magnitude greater than the daily re- quirement of the vitamin. A very limited amount of data suggests that the chronic administration of a sublethal dose of menadione can produce hemolytic anemia. The only indication of an adverse response to vitamin K ad- ministration in domestic animals appears to be the re- cent report of Rebhun et al. (1984) of acute renal failure in horses following the parenteral administration of a single dose of menadione bisulfite. This response was reproduced experimentally, and the dosage used was within the range recommended by the manufacturer of the compound. In contrast to the low but at least demonstrable toxic- ity of menadione, natural forms of vitamin K appear to be essentially innocuous. Molitor and Robinson (1940) administered up to 25 g/kg of BW of phylloquinone ei- ther parenterally or orally to laboratory animals with no reported adverse effect. Barash (1978) has reviewed re- ports of adverse effects on the cardiopulmonary system in humans following the intravenous injection of phyllo- quinone. This is an adverse drug reaction that occurs with very low frequency and may be a response to the colloid emulsion used as a vehicle rather than to the drug itself. The toxicity of menadione is undoubtedly not related to its role as a precursor for tissue synthesis of an active form of vitamin K but because of its chemical properties as a quinone. Vitamin K is routinely administered to prevent hemorrhagic disease of the newborn. At one time, menadione was the form of the vitamin widely used. A high incidence of hemolytic anemia and liver toxicity following this therapy (Finkel, 1961; Barash, 1978) has led to the recommendation (American Acad- emy of Pediatrics, 1971) of the administration of phyllo- quinone. The basis for the adverse reactions is not clear but is thought to be related to an influence on cellular redox state or sulfhydryl metabolism. PRESUMED UPPER SAFE LEVELS The limited amount of information available on vita- min K has failed to demonstrate any toxicity associated with the oral intake of phylloquinone and has shown that menadione can be ingested at levels as high as 1,000 times dietary requirements with no adverse effects. SUMMARY 1. Phylloquinone, a natural form of vitamin K, ex- hibits no adverse effects when administered to animals in massive doses by any route.

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34 4~ in: 4= c E c o so 4= be c o ~ En ._ ._ .= o a: ~ _ .s too ~ adz o o o o ~Lo o o o oo Loo o LO o o o o ~ ~ ~ ~ ~en ~ ~ ~ ~ ~ ~ cn ~ cr: ~ ~ ~ ~ ~ ~. - ~ ~ ~ ~ ~ ~ ~4 ~ ~ o o ~ ~ ~ ~ ~ o~ ~ ~ o ~ ~ o o o o ~o o ~ o oo ~ o o ~o o o o n CiD u~ cn - - ~it(~1 U} ~ C~ U)U) -~ U) U) - U;t C~) U) U: ~ .= .~: .= .= ~oo.~:: .= ~ .= .=.5 ~ .~ .~ ~.s . ~.= ~x ~ _ D D D Q ~D D _ D ~D ~_ . - . - ~D . - D ~D ~ 0 0 0 0 cn cr) ~0 0 ~ 0 00 ~ 0 0 ~0 0 0 ~0 (v 4 0< ~ ~ ~~^0< ~ a~ ~ ~P~ ~a~ ~ ~ 5 0< 0< ~- < ~:5 ~ i,,4 ~ ~ ~ ~ ~ ~ ^ C\S CT ~ S ~V cn ~ ~ ~ ~ ~ cn,5 ~ ~ U) S~ ~ ~ S~ ~ ~ ~ ~ ~ ~ ~S~ ~ ~S~ O O O O ~O O ~ O OO ~ O O ~O O O O ~ ~ ~ ~ ~ Ct t ~#_~ ~ ~ ~ ~ ~ ~ ~ tt ~ ~ 5 ~ ~ o o o o ~c: ~o o s~ o oo ~ o o ~o o o ~o <~ ~ ~ ~~ ~= ~ ~ V ~ ~ ~O ~- ~5~ ~ Y - ~ O E C ~^ Y O O O ~ ~ 0 b4 C\~^ cd ~ ~ C~ O ~o ~ ~c~ ~ ~ c~ {~^ ~ ~ ~0 o ~ ~ ~ ~ ~ ~: - 4= ~ ~ c~ ~ ~~ ~ c ~ a: a' ~au . _ ~ ~ ,- ~ ~ ~ ~ ~o ~ ~o ~i ~ o o ~o ~ ~ ~o CD ~ Z ~ CO ~ ~ ~ ~ ~ Z Z ~Z ~ ~Z i ~ ~ ~ C ~i~ ~ i~ a~ ~ ~ ~ ~ ~ a' cn u~ u~ co u~ co ~co cn cn u~ co cn u~ u ~cn u~ co o: ~ ~ ~ u ~ 0 0 0 0 0 0 ,[ ~0 0 0 0 0 0 0 0 0 0 0 0 _ _ _ 0 _ eo CO ~CO U ~ au a~ a ~a~ ~ ~ ~ a~ b~ ~ ~ b4 bO ~bC ~ to ~ b0 bC ?= b0 b0 ~ hO ~ ~ ~ tI.0 = ~ ~ ~ ~ ~ ~ ~ ~ ~ ~= = = ~m ._ ._ ._ ._ ._ ._ _ ._ ._ ._ ._ ._ ._ ._ ._ ._ ._ ._ ._ ._ ~?~ ~ ~ ~`ncn~ ~ ~`n~ ~a ~? ~ . ~c: ~C: v ~ v ~ ~ q.) a~ ~v OCR for page 31
Vitamin K 35 2. The toxic level of menadione or its derivatives in the diet is at least 1,000 times the dietary requirement. 3. Menadione or its derivatives, when administered parenterally, have an I~D50 in the range of a few hundred mg/kg of BW in all species studied except the horse. Doses of 2 to 8 mg/kg have been reported to be lethal in this species. REFERENCES Almquist, H. J.1975. The early history of vitamin K. Am. J. Clin. Nutr. 28:656. American Academy of Pediatrics, Committee on Nutrition. 1971. Vi- tamin K supplementation for infants receiving milk substitute in- fant formulas and for those with fat malabsorption. Pediatrics 48:483. Ansbacher, S., W. C. Corwin, and B. G. H. Thomas.1942. Toxicity of menadione, menadiol and esters. J. Pharmacol. Exp. Ther. 75:111. Barash, P. G. 1978. Nutrient toxicities of vitamin K. Pp. 97-100 in Handbook in Nutrition and Food, M. Rechcigl, ed. New York: CRC Press. Dam, H. 1929. Cholesterinstoffwechsel in Huhnereiern und Huchn- chen. Biochem. Z. 215:475. Dam, H.1964. The discovery of vitamin K, its biological functions and therapeutical application. Pp. 9-226 in Nobel Lectures Physiology or Medicine 1942-1962, Nobel Foundation, ed. New York: Elsevier. Doisy, E. A., and J. T. Matschiner. 1970. Biochemistry of vitamin K. Pp. 293-331 in Fat Soluble Vitamins, R. A. Morton, ed. Oxford: Pergamon Press. Esmon, C. T., J. A. Sadowski, and J. W. Suttie.1975. A new carboxyla- tion reaction. The vitamin K-dependent incorporation of H~4CO3 into prothrombin. J. Biol. Chem. 25:4744. Finkel, M. J. 1961. Vitamin K~ and the vitamin K analogues. Clin. Pharmacol. Ther. 2:794. Griminger, P. 1971. Nutritional requirements for vitamin K-animal studies. Pp.39-59 in Symposium Proceedings on the Biochemistry, Assay, and Nutritional Value of Vitamin K and Related Compounds. Chicago: Association of Vitamin Chemists. Hollander, D. 1981. Intestinal absorption of vitamins A, E, D, and K. J. Lab. Clin. Med. 97:449. MacCorquodale, D. W., L. C. Cheney, S. B. Binkley, W. F. Holcomb, R. W. McKee, S. A. Thayer, and E. A. Doisy.1939. The constitution and synthesis of vitamin K~. J. Biol. Chem. 131:357. Matschiner, J. T., R. G. Bell, J. M. Amelotti, and T. E. Knauer. 1970. Isolation and characterization of a new metabolite of phylloquinone in the rat. Biochim. Biophys. Acta 201:309. Molitor, H., and J. Robinson. 1940. Oral and parenteral toxicity of vitamin K~, phthiocol and 2-methyl 1,4-napthoquinone. Proc. Soc. Exp. Biol. Med. 43:125. Nelsestuen, G. L., T. H. Zytkovicz, and J. B. Howard.1974. The mode of action of vitamin K. Identification of ~y-carboxyglutamic acid as a component of prothrombin. J. Biol. Chem. 249:6347. Olson, R. E. 1980. Vitamin K. Pp. 170-180 in Modern Nutrition in Health and Disease, R. S. Goodhart and M. E. Shils, eds. Philadel- phia: Lea & Febiger. Rebhun, W. C., B. C. Tennant, S. G. Dill, and J. M. King. 1984. Vitamin K3-induced renal toxicosis in the horse. J. Am. Vet. Med. Assoc. 184:1237. Richards, R. K., and S. Shapiro.1945. Experimental and clinical stud- ies on the action of high doses of hykinone and other menadione derivatives. J. Pharmacol. Exp. Ther. 84:93. Scott, M. L. 1966. Vitamin K in animal nutrition. Vit. Horm. 24:633. Shearer, M. J., A. McBurney, and P. Barkhan. 1974. Studies on the absorption and metabolism of phylloquinone (vitamin K~) in man. Vit. Horm. 32:513. Smith, J. J., A. C. Ivy, and R. H. K. Foster.1943. The pharmacology of two water-soluble vitamin K-like substances. J. Lab. Clin. Med. 28:1667. Stenflo, J., P. Fernlund, W. Egan, and P. Roepstorff. 1974. Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc. Natl. Acad. Sci. U.S.A. 71:2730. Suttie, J. W. 1985a. Vitamin K. Pp. 225-311 in The Fat-soluble Vita- mins, A. T. Diplock, ed. London: William Heinemann Ltd. Suttie, J. W. 1985b. Vitamin K-dependent carboxylase. Annul Rev. Biochem. 54:459.