Vita VITAMIN D Liver25-OH-as Pi other 25-OHD Kidne Parathyroid glands phosphorus Fig 3. 2 Metabolism of vitamin D and the biological actions of 1, 25 dihydroxyvitamin D(1, 25-OHD) in raising blood calcium from bone resorption and/or the intestinal absorp- tion. The figure shows the stimulatory role of parathyroid hormone(PTH) on kidney thesis of 1, 25-OHd and the feedback inhibition. (From Holick MF, ' McCollum Award Lecture, 1994: vitamin D-new horizons for the 21st century, Am Clin Nutr, 1994, 60 619-30)(Reproduced with permission by the American Journal of Clinical Nutrition Am J Clin Nutr. American Society for Clinical Nutrition the circulating level of parathyroid hormone(PTH), plasma calcium concentra- tions and the current vitamin D status of the body. In response to PTH in the vitamin D-deficient state, 1, 25-OHD production is high(and this directly induces eedback inhibition of PTH production within the parathyroid gland) and 24, 25 OHD is low. In the vitamin D-adequate state, Ia-hydroxylase activity in the kidney is increased and more 24, 25-OHD is produced. Again, 1, 25-OHD directly reduces PTH production in the parathyroid gland(Fig. 3.2). Under most circum stances the principal site for 1, 25-OHD production is the kidney; however, during
the circulating level of parathyroid hormone (PTH), plasma calcium concentrations and the current vitamin D status of the body. In response to PTH in the vitamin D-deficient state, 1,25-OHD production is high (and this directly induces feedback inhibition of PTH production within the parathyroid gland) and 24,25 OHD is low. In the vitamin D-adequate state, 1a-hydroxylase activity in the kidney is increased and more 24,25-OHD is produced. Again, 1,25-OHD directly reduces PTH production in the parathyroid gland (Fig. 3.2). Under most circumstances the principal site for 1,25-OHD production is the kidney; however, during Vitamins 49 Blood calcium & phosphorus Parathyroid glands Kidney Liver C alcification Intestine Bone VITAMIN D 25-OH-ase 1a-OH-ase PTH PTH Ca++HPO4 - Ca++HPO4 - Pi & other factors 25-OHD 1,25 OHD 1,25 OHD Fig. 3.2 Metabolism of vitamin D and the biological actions of 1,25 dihydroxyvitamin D (1,25-OHD) in raising blood calcium from bone resorption and/or the intestinal absorption. The figure shows the stimulatory role of parathyroid hormone (PTH) on kidney synthesis of 1,25-OHD and the feedback inhibition. (From Holick MF, ‘McCollum Award Lecture, 1994: vitamin D – new horizons for the 21st century’, Am J Clin Nutr, 1994, 60, 619–30) (Reproduced with permission by the American Journal of Clinical Nutrition. © Am J Clin Nutr. American Society for Clinical Nutrition.)
60 The nutrition handbook for food processors pregnancy the placenta also seems to have a role in producing it at the time of increased calcium requirements by the foetus(Loveridge, 2000) Vitamin D maintains plasma calcium concentrations by stimulating intestinal calcium abso rption by the small intestine and/or the resorption of calcium from bone. Calcium transport across intestinal cells is stimulated by 1, 25-OHD by inducing the production of calcium binding protein( CBP)within the villous cells, and inducing an extremely low concentration of cystolic calcium within the enterocyte. 1, 25-OHD also promotes cell maturation within the intestine (Suda et al, 1990) and in studies using vitamin D-deficient rats, villous length is only 70%0 of that of normal rats. Serum calcium is tightly controlled but a number of studies suggest it peaks in the summer perhaps because of improved vitamin D status, growth stimulation in children and higher intestinal calcium absorption (McCance and Widdowson, 1943). More recent studies, using radio-isotopes, have shown fractional calcium absorption was significantly higher in post menopausal women evaluated from August to October than from March to May (Krall and Dawson-Hughes, 1991). In addition, increased intestinal calcium retention was associated with a lower rate of bone loss from the radius. The changes in calcium absorption and excretion could be accounted for by small sea- sonal increases in 1. 25 ohd during the summer months found in some of the studies(Sherman et al, 1990) 3.11 Bone mineral density and fractures In the presence of adequate dietary calcium, 1, 25-OHD increases bone formation and growth plate mineralisation by providing sufficient calcium to allow calcifi- cation to occur. In contrast, prolonged vitamin D deficiency results in a poorly mineralised skeleton. When calcium is limited the skeleton is sacrificed because appropriate concentrations of calcium are required for vital nerve and muscle activity. Seasonal increases in PTH may have an adverse effect on bone loss. It is known that accelerated bone loss occurs in hyperparathyroidism(Maxwell 2001)and increased PTH activity is a determinant in vertebral osteoporosis However, studies by Krall and Dawson-Hughes (1991) showed that serum con- centrations of 25-OHD >95 nmol/L prevent a seasonal increase in PTH. This sug gests that when vitamin D status is poor, PTH stimulates 1, 25-OHD production, which acts primarily on the bone to release calcium for essential activities. When vitamin D status is good, sufficient 1, 25-OHD is produced to stimulate intestinal absorption of calcium so the bone is spared In the UK and the USA, seasonal changes in hip fractures have been recog nised with peak fracture rates occurring during the winter months. The role of vitamin D deficiency in the pathogenesis of osteoporotic fractures is controver- sial and the inverse association with hip fracture rates could just be coincidence However, seasonal changes in bone mineral density(Krolner, 1983) and the inverse seasonal changes in PTH, could be related to the accelerated bone loss In addition, vitamin D is known to regulate the synthesis of osteocalcin(Reichel
pregnancy the placenta also seems to have a role in producing it at the time of increased calcium requirements by the foetus (Loveridge, 2000). Vitamin D maintains plasma calcium concentrations by stimulating intestinal calcium absorption by the small intestine and/or the resorption of calcium from bone. Calcium transport across intestinal cells is stimulated by 1,25-OHD by inducing the production of calcium binding protein (CBP) within the villous cells, and inducing an extremely low concentration of cystolic calcium within the enterocyte. 1,25-OHD also promotes cell maturation within the intestine (Suda et al, 1990) and in studies using vitamin D-deficient rats, villous length is only 70% of that of normal rats. Serum calcium is tightly controlled but a number of studies suggest it peaks in the summer perhaps because of improved vitamin D status, growth stimulation in children and higher intestinal calcium absorption (McCance and Widdowson, 1943). More recent studies, using radio-isotopes, have shown fractional calcium absorption was significantly higher in postmenopausal women evaluated from August to October than from March to May (Krall and Dawson-Hughes, 1991). In addition, increased intestinal calcium retention was associated with a lower rate of bone loss from the radius. The changes in calcium absorption and excretion could be accounted for by small seasonal increases in 1,25 OHD during the summer months found in some of the studies (Sherman et al, 1990). 3.11 Bone mineral density and fractures In the presence of adequate dietary calcium, 1,25-OHD increases bone formation and growth plate mineralisation by providing sufficient calcium to allow calcifi- cation to occur. In contrast, prolonged vitamin D deficiency results in a poorly mineralised skeleton. When calcium is limited the skeleton is sacrificed because appropriate concentrations of calcium are required for vital nerve and muscle activity. Seasonal increases in PTH may have an adverse effect on bone loss. It is known that accelerated bone loss occurs in hyperparathyroidism (Maxwell, 2001) and increased PTH activity is a determinant in vertebral osteoporosis. However, studies by Krall and Dawson-Hughes (1991) showed that serum concentrations of 25-OHD >95 nmol/L prevent a seasonal increase in PTH. This suggests that when vitamin D status is poor, PTH stimulates 1,25-OHD production, which acts primarily on the bone to release calcium for essential activities. When vitamin D status is good, sufficient 1,25-OHD is produced to stimulate intestinal absorption of calcium so the bone is spared. In the UK and the USA, seasonal changes in hip fractures have been recognised with peak fracture rates occurring during the winter months. The role of vitamin D deficiency in the pathogenesis of osteoporotic fractures is controversial and the inverse association with hip fracture rates could just be coincidence. However, seasonal changes in bone mineral density (Krolner, 1983) and the inverse seasonal changes in PTH, could be related to the accelerated bone loss. In addition, vitamin D is known to regulate the synthesis of osteocalcin (Reichel 50 The nutrition handbook for food processors
Vita et al, 1989), the matrix protein in bone, thus a causal association between low 25-OHD levels and osteoporosis in postmenopausal women(Villareal et al, 199 is possible(see also sections 3.20.2 and 3.21.3) 3. 12 Vitamin D and other aspects of health 3.12.1 Behaviour Specific vitamin D receptors are found in parts of the brain and spinal cord Maxwell, 2001). Seasonal changes in 25-OHD and 1, 25-OHD could have an effect on hormonal function, mood and behaviour. For example, seasonal affec tive disorders(SAD) appear to have a latitude gradient, with mood changes due to a reduction in daylight hours and altered circadian secretion of melatonin Whether seasonal changes in UV light and vitamin D contribute is unknown 3.12.2 Colon cancer Mortality rates from colon cancer are highest in those areas that receive the least amount of sunlight. A prospective study of 26000 volunteers investigated the association between 25-OHD and the risk of colon cancer. In those with 25-OHD concentrations of 50nmoI/L (20ng/ml or more, the risk of colon cancer was decreased threefold. However, confounding factors such as consumption of milk meat or fat in the diet were not considered but these observations and previous epidemiological and laboratory studies suggest good vitamin D status in con- junction with calcium nutrition might lower the risk of colon cancer(Garland etal,1989) 3.12.3 The immune system Experimental evidence from animals, both in vitro and in vivo, has shown an immunological role for 1, 25 OHD, in both lymphocytes and monocytes(Yang et al, 1993). Strict lactovegetarians, particularly in immigrant Asians, have an 8.5 fold increased risk of tuberculosis compared with those who ate meat or fish dail Since vitamin d deficiency is more common among vegetarian Asians and it is known to have effects on immunological function in animals, vitamin d defi iency may be responsible for reduced immunocompetence(Maxwell, 2001). The mechanism for the immunological role of vitamin d is not known, but e hormone receptor for 1, 25-OHD is now recognised as one of a superfamily, the so-called "Steroid-Thyroid-Retinoid-Superfamily'. It is understood that if these nuclear receptors and their activating substances are to recognise response elements within responsive genes, they must act in pairs and a member of the retinoid family must serve as a partner if the dimer is to function. Thus vitamin A, usually in the form of retinoic acid, is a regulator for several hormone response systems including vitamin D(Kliewer et al, 1994)(see section 3.5.2). The anti-infection properties of vitamin A are widely recognised and interactions
et al, 1989), the matrix protein in bone, thus a causal association between low 25-OHD levels and osteoporosis in postmenopausal women (Villareal et al, 1991) is possible (see also sections 3.20.2 and 3.21.3). 3.12 Vitamin D and other aspects of health 3.12.1 Behaviour Specific vitamin D receptors are found in parts of the brain and spinal cord (Maxwell, 2001). Seasonal changes in 25-OHD and 1,25-OHD could have an effect on hormonal function, mood and behaviour. For example, seasonal affective disorders (SAD) appear to have a latitude gradient, with mood changes due to a reduction in daylight hours and altered circadian secretion of melatonin. Whether seasonal changes in UV light and vitamin D contribute is unknown. 3.12.2 Colon cancer Mortality rates from colon cancer are highest in those areas that receive the least amount of sunlight. A prospective study of 26 000 volunteers investigated the association between 25-OHD and the risk of colon cancer. In those with 25-OHD concentrations of 50 nmol/L (20 ng/ml) or more, the risk of colon cancer was decreased threefold. However, confounding factors such as consumption of milk, meat or fat in the diet were not considered but these observations and previous epidemiological and laboratory studies suggest good vitamin D status in conjunction with calcium nutrition might lower the risk of colon cancer (Garland et al, 1989). 3.12.3 The immune system Experimental evidence from animals, both in vitro and in vivo, has shown an immunological role for 1,25 OHD3 in both lymphocytes and monocytes (Yang et al, 1993). Strict lactovegetarians, particularly in immigrant Asians, have an 8.5- fold increased risk of tuberculosis compared with those who ate meat or fish daily. Since vitamin D deficiency is more common among vegetarian Asians and it is known to have effects on immunological function in animals, vitamin D defi- ciency may be responsible for reduced immunocompetence (Maxwell, 2001). The mechanism for the immunological role of vitamin D is not known, but the hormone receptor for 1,25-OHD is now recognised as one of a superfamily, the so-called ‘Steroid-Thyroid-Retinoid-Superfamily’. It is understood that if these nuclear receptors and their activating substances are to recognise response elements within responsive genes, they must act in pairs and a member of the retinoid family must serve as a partner if the dimer is to function. Thus vitamin A, usually in the form of retinoic acid, is a regulator for several hormone response systems including vitamin D (Kliewer et al, 1994) (see section 3.5.2). The anti-infection properties of vitamin A are widely recognised and interactions Vitamins 51
52 The nutrition handbook for food processors between vitamins A and D status may therefore be important in regulating immune function 3.13 Safety Infants are most at risk of developing hypervitaminosis D. There are some reports of hypercalcaemia in infants given 50ug vitamin D/day and mild hypercalcaemia at doses of 15 mg orally every 3-5 months(Department of Health, 1991) 3.14 Vitamin E In 1922, a factor X, an antisterility factor, was found to be a fat-soluble compo- nent and essential for prevention of foetal death and sterility in rats. Vitamin E, as it became known, was isolated from wheat germ in 1936 and given its present name, tocopherol from the Greek words'tokos'and'pherein'which means'to bring forth children. It is now known that there are several forms of tocopherol and the term vitamin E is used to denote any mixture of biologically active tocopherols. Vitamin E activity is currently defined in mg a-tocopherol equiva lents(a-TE) where 1 mg a-tE equals the activity of I mg RRR-a-tocopherol Formerly international units (u) were used and vitamin E is still occasionally quoted in this way in clinical trials. Where DL-a-tocopherol acetate is used, 1IU equals 0.67 mg C-TE (Duthie, 2000) There are eight naturally-occurring vitamin E compounds, four tocopherols and four tocotrienols, all synthesised by plants. The tocopherols are quantitatively and physiologically the more important. The most active of these compounds is a-tocopherol, which accounts for 90% of the vitamin E present in human tissues Vegetable oils are the major sources of tocopherols. Sunflower and olive oil contain mainly a-tocopherol while in soya oil, the y form accounts for 60% of total tocopherol. Other food groups provide substantial amounts of a-tocopherol including meat, fruit, nuts, cereals and eggs (Table 3.2). There is a widely available synthetic form of vitamin E, DL-a-tocopherol that consists of eight stereoisomers in approximately equal amounts. The synthetic form is used in animal feeds and is available in capsule form as a supplement for humans. Toco- pherols and tocotrienols are readily oxidised to quinones, dimers and trimers by light, heat, alkali and divalent metals such as copper and iron so synthetic prepa- rations are often protected by acetylation and succinylation(Duthie, 2000) The assessment of vitamin e status is difficult because clinical signs of defi- ciency are not often seen, except occasionally in premature babies or in persons with fat malabsorption. This suggests that modern diets, which provide approxi mately 10 mg vitamin E/d in the UK are adequate( Gregory et al, 1990). However, epidemiological evidence that intakes of vitamin E and other antioxidants are inversely correlated with the risk of some cancers and heart disease have led to some suggestions that optimal intake should be more than DRVs
between vitamins A and D status may therefore be important in regulating immune function. 3.13 Safety Infants are most at risk of developing hypervitaminosis D. There are some reports of hypercalcaemia in infants given 50mg vitamin D/day and mild hypercalcaemia at doses of 15 mg orally every 3–5 months (Department of Health, 1991). 3.14 Vitamin E In 1922, a factor X, an antisterility factor, was found to be a fat-soluble component and essential for prevention of foetal death and sterility in rats. Vitamin E, as it became known, was isolated from wheat germ in 1936 and given its present name, tocopherol from the Greek words ‘tokos’ and ‘pherein’ which means ‘to bring forth children’. It is now known that there are several forms of tocopherol and the term vitamin E is used to denote any mixture of biologically active tocopherols. Vitamin E activity is currently defined in mg a-tocopherol equivalents (a-TE) where 1 mg a-TE equals the activity of 1 mg RRR-a-tocopherol. Formerly international units (IU) were used and vitamin E is still occasionally quoted in this way in clinical trials. Where dl-a-tocopherol acetate is used, 1 IU equals 0.67 mg a-TE (Duthie, 2000). There are eight naturally-occurring vitamin E compounds, four tocopherols and four tocotrienols, all synthesised by plants. The tocopherols are quantitatively and physiologically the more important. The most active of these compounds is a-tocopherol, which accounts for 90% of the vitamin E present in human tissues. Vegetable oils are the major sources of tocopherols. Sunflower and olive oil contain mainly a-tocopherol while in soya oil, the g form accounts for 60% of total tocopherol. Other food groups provide substantial amounts of a-tocopherol including meat, fruit, nuts, cereals and eggs (Table 3.2). There is a widely available synthetic form of vitamin E, dl-a-tocopherol that consists of eight stereoisomers in approximately equal amounts. The synthetic form is used in animal feeds and is available in capsule form as a supplement for humans. Tocopherols and tocotrienols are readily oxidised to quinones, dimers and trimers by light, heat, alkali and divalent metals such as copper and iron so synthetic preparations are often protected by acetylation and succinylation (Duthie, 2000). The assessment of vitamin E status is difficult because clinical signs of defi- ciency are not often seen, except occasionally in premature babies or in persons with fat malabsorption. This suggests that modern diets, which provide approximately 10 mg vitamin E/d in the UK are adequate (Gregory et al, 1990). However, epidemiological evidence that intakes of vitamin E and other antioxidants are inversely correlated with the risk of some cancers and heart disease have led to some suggestions that optimal intake should be more than DRVs. 52 The nutrition handbook for food processors
Vitami Vitamin E status can be measured as plasma tocopherol concentration but increased concentration of serum lipids appears to cause tocopherol to leave cell membranes and go into the circulation hence increasing blood levels. Because of his, plasma tocopherol is usually expressed in relation to circulating lipids, the most commonly used ratio being serum tocopherol: cholesterol. Values for serum a-tocopherol s11. 6umol/L or of the a-tocopherol: cholesterol ratio $2.2 umol/mmol indicate a risk of vitamin E inadequacy (Thurnham et al, 1986) 3. 15 Biological activity The biological activity of vitamin E is almost entirely due to its antioxidant prop erties. In vivo vitamin E appears to be the major lipid-soluble antioxidant component in membranes and is particularly effective in preventing lipid perox- idation, which is a series of chemical reactions involving the oxidative deterio- ration of polyunsaturated fatty acids(PUFA). Lipid peroxidation may cause the disruption of cell structure and function and may play an important role in the etiology of many diseases e.g. heart disease and cancer. In biological systems the peroxidative cascade is likely to be terminated by vitamin E PUFA:H+R·=PUFA·+RH Non-radical PUFA+ Free radical PUFA Radical Non-radical product PUFA·+O,= PUFAOC [3.2 PUFA Radical oxygen= peroxyl PUFA Radical tocopherol-OH PUFAOO.= tocopherol-O. PUFAOOH [3.3 tocopheroxy radical lipid hydroperoxide When vitamin e donates hydrogen it becomes a free radical but is relativel reactive and the chain reaction is halted because the unpaired electron on the oxygen atom becomes delocalised within the aromatic ring structure. The con centration of vitamin E in cell membranes is low, about I molecule for every 2000 phospholipid molecules, therefore in order for vitamin E to continue to protect the membranes, it must be reduced to its original structure by vitamin C or other reducing compounds in the immediate environment. Likewise, lipid hydroperoxide has to be removed from the membrane for although it is semi- stable, its structure is altered by oxidation and it is potentially pro-oxidative in the presence of transition metals. Lipid hydroperoxides can be released from the phospholipid structure in membranes by phospholipase A2 and then degraded by elenium-dependent glutathione peroxidase in the cytoplasm or associated with the cell membrane( Chaudiere and Ferrari-nliou, 1999) 3.16 Coronary heart disease(CHD) pidemiological studies have reported an inverse relationship between the inci- dence of CHD and vitamin E status using a variety of methods. A descriptive
Vitamin E status can be measured as plasma tocopherol concentration but increased concentration of serum lipids appears to cause tocopherol to leave cell membranes and go into the circulation hence increasing blood levels. Because of this, plasma tocopherol is usually expressed in relation to circulating lipids, the most commonly used ratio being serum tocopherol :cholesterol. Values for serum a-tocopherol £11.6mmol/L or of the a-tocopherol :cholesterol ratio £2.2 mmol/mmol indicate a risk of vitamin E inadequacy (Thurnham et al, 1986). 3.15 Biological activity The biological activity of vitamin E is almost entirely due to its antioxidant properties. In vivo vitamin E appears to be the major lipid-soluble antioxidant component in membranes and is particularly effective in preventing lipid peroxidation, which is a series of chemical reactions involving the oxidative deterioration of polyunsaturated fatty acids (PUFA). Lipid peroxidation may cause the disruption of cell structure and function and may play an important role in the aetiology of many diseases e.g. heart disease and cancer. In biological systems the peroxidative cascade is likely to be terminated by vitamin E: PUFA :H + R• = PUFA• + RH [3.1] Non-radical PUFA + Free radical = PUFA Radical + Non-radical product PUFA• + O2 = PUFAOO• [3.2] PUFA Radical + oxygen = peroxyl PUFA Radical tocopherol-OH + PUFAOO• = tocopherol-O• + PUFAOOH [3.3] = tocopheroxy radical + lipid hydroperoxide When vitamin E donates hydrogen it becomes a free radical but is relatively unreactive and the chain reaction is halted because the unpaired electron on the oxygen atom becomes delocalised within the aromatic ring structure. The concentration of vitamin E in cell membranes is low, about 1 molecule for every 2000 phospholipid molecules, therefore in order for vitamin E to continue to protect the membranes, it must be reduced to its original structure by vitamin C or other reducing compounds in the immediate environment. Likewise, lipid hydroperoxide has to be removed from the membrane for although it is semistable, its structure is altered by oxidation and it is potentially pro-oxidative in the presence of transition metals. Lipid hydroperoxides can be released from the phospholipid structure in membranes by phospholipase A2 and then degraded by selenium-dependent glutathione peroxidase in the cytoplasm or associated with the cell membrane (Chaudiere and Ferrari-Iliou, 1999). 3.16 Coronary heart disease (CHD) Epidemiological studies have reported an inverse relationship between the incidence of CHD and vitamin E status using a variety of methods. A descriptive Vitamins 53