Donald B McCormick

Department of Biochemistry, School of Medicine, Emory University, Atlanta, Georgia, USA

Overview and Focus

Coverage of what is known about the intracellular trafficking and compartmentalization of the numerous and diverse nutrients that must be supplied to the different cells that comprise many higher organisms, especially such complex mammals as humans, cannot be detailed in a single chapter. The molecular processes and pathways by which macro- and micronutrients are transported and utilized within a cell continue to be summarized in textbooks on biochemistry and nutrition. Suitable examples that treat material that pertains to the human can be found in current editions of a Textbook of Biochemistry with Clinical Correlations edited by Devlin (Wiley-Liss, New York) and Modern Nutrition in Health and Disease edited by Shils et al. (Williams and Wilkins, Baltimore). Chapters updating these subjects are in the Annual Review of Biochemistry, Annual Review of Nutrition and such compendia as Present Knowledge in Nutrition and review chapters in research journals.

It will be the purpose ofthis chapter to restrict the scope such that at least the main points ofwhat has been learnt about the subject as concerns vitamins can be brought together. This apparently has not been done previously for the particular focus of intracellular trafficking and compart-mentalization. Some disconnected statements on this subject can be found in texts and treatises on vitamins, e.g. the third edition of the Handbook of

©CAB International 2003. Molecular Nutrition (eds J. Zempleni and H. Daniel)

Vitamins (Marcel Dekker, New York), which describe many aspects of these essential micronutrients.

Because classically considered vitamins function usually after metabolism to physiologically active forms, i.e. coenzymes or hormones, it is appropriate that aspects of these conversions and subsequent compartmentalizations be included as well. For cohesiveness, it seems reasonable to cover each under the subdivision of the particular vitamin and its functional forms. Events covered are those that occur upon uptake through the plasma membrane ofa eukaryotic cell, the subsequent partitioning into cytosol and organelles (mitochondria, endoplasmic reticulum, lysozomes, nucleus, etc.), and those metabolic alterations that are involved.

Vitamin A

Upon intestinal mucosal cell uptake ofdietary precursors of vitamin A, namely pro-A carotenoids with a b-ionone ring, they are converted both by the dioxygenase-catalysed endocentric cleavage of the 15,15' double bond to yield retinal and by eccentric cleavage to b-apocarotenals, which are oxidized further to retinal (Olson, 2001). NAD-dependent dehydrogenases reduce the retinal to its alcohol, which, together with retinol derived from the diet, is largely converted to retinyl esters.

The latter are incorporated into chylomicrons, which are released into the lymph. The uptake of retinyl esters by the liver leads to ester-catalysed hydrolysis followed by complexing of the released retinol with cytoplasmic retinol-binding proteins. Some of the all-trans-retinol in liver parenchymal cells binds with a specific protein (RBP) that, together with transthyretin, is secreted into the plasma for distribution to cells in other tissues. Within both the cytosol and the nucleus of the cells, the retinol and a fraction oxidized in the cytosol to retinal and retinoic acid are bound to diverse cytosolic retinoid-binding proteins that are listed in Table 4.1.

The properties and functions ofthese proteins are considered in reviews (Ong et al, 1994; Saari, 1994; Newcomer, 1995; Li and Norris, 1996). Cellular retinol-binding protein I (CRBP I) and II and cellular retinoic acid-binding protein I (CRABP I) and II are fairly small proteins (15.0-15.7 kDa) that vector the all-trans isomers. In the intestinal cell, CRBP I and II selectively direct retinol for esterification by lecithin:retinol acyltransferase (LRAT) over acyl-CoA:retinol acyltransferase (ARAT). CRABP I is found in many tissues, but CRABP II expression is localized to skin of the adult animal. Both CRBP I and II are influenced by retinoid nutritional status (Kato, 1985). In the small intestine of the retinoid-deficient rat, the mRNA for CRBP I is reduced, whereas that for CRBP II is increased. CRALBP (36 kDa) and IRBP (135 kDa) function as transporters of the 11-cis isomers within the retinal cells. The ERABP (18.5 kDa) vectors all-trans and 9-cis-retinoic acid within testicular cells. The CRBPs influence retinoid signalling pathways by modulating intracellular retinoid metabolism and by influencing ligand occupancy of the nuclear receptors.

Upon entry of retinoic acids (all- trans and 9-cis) and other retinoids into the nucleus, they are tightly bound to one or more of the three (a, b, g) retinoic acid receptors (RARs) or retinoid X receptors (RXRs). These receptors, like others for hormones binding in the nucleus, possess six protein domains (designated A-F in progressing from the N- to the C-terminus) with specific functions. The E region binds the ligand. For both RAR and RXR, the hormone response element (HRE) in DNA is the consensus sequence AGGTCA. Many genes contain response elements for the retinoid receptors. Notable effects include: stimulation of both certain cytosolic and nuclear binding proteins for retinoids by retinoic acid via retinoic acid response elements; stimulation of Hox a-1 (Hox 1.6) and Hox b-1 (Hox 2.9) initiating genes of embryonic development; and enhancement of class I alcohol dehydrogenase type 3 inducing the conversion of retinol to more retinoic acid.

Vitamin D (Calciferols)

Processing of vitamin D, which is a prohormone, requires specific and successive events within different tissues (Collins and Norman, 2001). For D3 (cholecalciferol), 7-dehydrocholesterol located primarily within the Malpighian layer of dermal cells is converted in a natural process that involves light-induced fission of the B ring at the 9,10 bond to form provitamin D3. In the formation of D2 (ergocalciferol), plant-derived ergosterol, which has a 22,23-D-24-methyl side chain, is altered photochemically in an artificial process that is similar to what transpires when 7-dehydrocholesterol is converted to D3. The artificial D2 is used for the enrichment of milk and dairy products. Both natural and artificial forms of vitamin D are hydroxylated and converted to hormonally active

Table 4.1. Cellular retinoid-binding proteins.

Name (abbrevation)

Major ligand

Cellular retinol-binding protein, type I (CRBP I) Cellular retinol-binding protein, type II (CRBP II) Cellular retinoic acid-binding protein, type I (CRABP I) Cellular retinoic acid-binding protein, type II (CRABP II) Epididymal retinoic acid-binding protein (ERABP) Cellular retinaldehyde-binding protein (CRALBP) Interphotoreceptor retinol-binding protein (IRBP)

All-trans-retinol All-trans-retinol All-trans-retinoic acid All-trans-retinoic acid All-trans and 9-c/s-retinoic acid 11-c/s-retinol and retinal 11-c/s-retinal and all-trans-retinol derivatives. Vitamin D is transported, bound to a specific protein in plasma, primarily to the liver, where 25-hydroxylation is catalysed by a P450-like hydroxylase in microsomes and mitochondria (Saarem et al., 1984). From the liver, the 25-hydroxy-D is carried as the plasma complex with the D-binding protein to the kidneys, where 1a-hydroxylation occurs in the mitochondria of proximal tubular cells. The 25-hydroxy-D 1a-hydroxylase is a mixed-function oxidase that uses molecular oxygen (Henry and Norman, 1974). The enzyme is comprised of three proteins (renal ferredoxin, its reductase and a cytochrome P450) that are integral components of the mito-chondrial membrane. The control of the renal 1 a-hydroxylase is the most important point ofreg-ulation in the vitamin D endocrine system (Henry, 1992). Major factors are the product 1a,25-dihydroxy-D, parathyroid hormone (PTH), and the serum concentrations of Ca2+ and phosphate (Henry et al., 1992). Besides the natural, hormonally active dihydroxy-D, there are nearly 40 known metabolites ofD3. Most are inactive and excreted in the faeces. However, the 24R,25-dihydroxy-D3, which is also produced in the kidneys, is probably required along with 1a,25-dihydroxy-D3 for some of the biological responses to vitamin D, for example in the mineralization of bone and egg shells (Collins and Norman, 2001). As for storage of vitamin D3, there is some variation among species, but in the human, adipose tissue serves predominantly as a storage site for D3, whereas muscle retains significant 25-hydroxy-D3 (Mawer et al, 1972). The 1a,25-dihydroxy-D3 is catabolized via a number of pathways that lead to its rapid removal from the organism (Kumar, 1986). Upon protein-vectored transport of 1a,25-dihydroxy-D through plasma to target tissues, the hormone interacts with specific, high-affinity, intracellular receptors, first in the cytosol and then in the nucleus. Over two dozen target tissues and cells have been reported to have high-affinity receptors for 1a,25-dihydroxy-D3 (Collins and Norman, 2001). The nuclear receptor for this hormone (VDR), first discovered in the intestines of vitamin D-deficient chicks, was found to be a 50 kDa DNA-binding protein that belongs to a superfamily of homologous nuclear receptors. As in the case of the nuclear receptors for vitamin A, the E domain toward the C-terminus of VDR binds the dihydroxy-D. As a group II receptor, VDR (like RAR and RXR) can form hetero-dimers with other receptors. This enhances the diversity of physiological effects.

The nuclear receptor-hormone complex is activated and binds to an HRE on the DNA to modulate expression of hormone-sensitive genes. Modulation of gene transcription results in induction or repression of specific mRNAs, which leads to changes in protein expression ultimately reflected in biological responses. More than 50 genes are known to be regulated by 1a,25-dihydroxy-D3 (Hannah and Norman, 1994). Some of those that were registered by changes in the mRNA level as well as in intestinal or renal tissue are noted in Table 4.2.

Among those proteins that are increased by D action is calbindin. The genomic induction of this

Table 4.2. Some genes in intestine and kidney regulated by 1a,25-dihydroxy-D3

Gene

Tissue

Regulation

a-Tubulin

Intestine

Down

Aldolase subunit B

Kidney

Up

Alkaline phosphatase

Intestine

Up

ATP synthase

Intestine, kidney

Up, down

Calbindin 9K and 28K

Intestine, kidney

Up

Cytochrome oxidase subunits I, II and III

Intestine, kidney

Up, down

Cytochrome b

Kidney

Down

Ferridoxin

Kidney

Down

1-Hydroxy-D 24-hydroxylase

Kidney

Up

Metallothionein

Kidney

Up

NADH dehydrogenase subunit I

Kidney, intestine

Down, up

subunits III and IV

Plasma membrane Ca2+ pump

Intestine

Up

VDR

Intestine

Up

calcium-binding protein is one of the major effects of 1a,25-dihydroxy-D3. In addition, there are non-genomic actions of the dihydroxy-D that precede its slower hormonal response. The rapid transport of Ca2+ mediated by dihydroxy-D is termed 'transcaltachia' (Nemere and Norman, 1987). In the intestine, this process appears to involve inter-nalization of Ca2+ in endocytic vesicles at the brush border membrane, which then fuse with lysosomes and travel along microtubules to the basal lateral membrane for exocytosis. Other non-genomic actions of dihydroxy-D may include phospho-inositide breakdown. It is now clear that vitamin D, largely through the action of its 1a,25-dihydroxy metabolite, has a range of actions, with a central role in the intestinal absorption of Ca2+ and the mineralization of bone.

Vitamin E

The eight members of the vitamin E group, which includes four tocopherols (a, b, g, 8) and four tocotrienols (a, b, g, 8), are biosynthesized only by plants and are found at especially high levels in edible vegetable oils (Sheppard et al., 1993). Biologically, the most active form is RRR- (formerly designated d-) a-tocopherol, and most studies have dealt with the properties of this form of E. Absorption of E from the lumen of the small intestine is a passive diffusion, non-carrier-mediated process with relatively low efficiency (Traber and Sies, 1996; Chow, 2001). Within the enterocyte, vitamin E is incorporated into chylomicrons and secreted into the intracellular spaces and lymphatic system. Upon conversion of chylomicrons to remnant particles, E is distributed to circulating lipoproteins and ultimately to tissues. Liver parenchymal cells take up the remnants after chylomicrons are partially delipidated by lipopro-tein lipase and there is acquisition of apoE. Liver is responsible for the control and packaging of tocopherol with very low-density lipoproteins (VLDLs). Cytosolic a-tocopherol transfer proteins, first identified in rat liver (Catignani and Bieri, 1977) and more recently characterized from the cDNA sequence in human liver (Arita et al., 1995), exhibit selectivity for the RRR-a-tocopherol that is transferred to VLDLs. The purified rat liver protein with a molecular mass of 30-36 kDa has two isoforms (Sato et al., 1991)

and facilitates transfer of a-tocopherol between membranes. The human liver protein with similar action has a molecular mass of 36.6 kDa (Kuhlenkamp et al., 1993). A smaller (14.2 kDa) a-tocopherol-binding protein from liver and heart may be involved in intracellular transport and metabolism of a-tocopherol (Gordon et al., 1995).

From the liver, tocopherol-bearing VLDLs are secreted into plasma for delivery to peripheral tissues. Lipoproteins that are associated with E in plasma exchange tocopherol to cells at least partly via receptors, though specific mechanisms are not fully understood (Traber and Sies, 1996; Chow, 2001). Most tissues have the capacity to accumulate a-tocopherol, though none functions as a storage organ. Much of the vitamin E in the body is localized in the adipose tissue where tocopherol is mainly in the bulk lipid droplet from which turnover is slow. Turnover is also slow from muscle, testes, brain and the spinal cord. Adrenal glands have the highest concentration of a-tocopherol, although lungs and spleen also contain relatively high concentration. a-Tocopherol is taken up and located primarily in parenchymal cells (Bjorneboe et al., 1991), whereupon some transfer to non-parenchymal cells can occur. Parenchymal cells can store surplus tocopherol and are depleted less readily than non-parenchymal cells. Within a cell, light mitochondria have the highest concentration of a-tocopherol, whereas the concentration is low in cytosol. The majority of tocopherol is located in membranes, including those of erythrocytes from which turnover is relatively rapid. Approximately three-quarters of mitochondrial a-tocopherol is found in the outer membrane, and one-quarter is associated with the inner membrane.

Upon exerting its antioxidant action, tocopherol is converted to the tocopheryl chromanoxy radical (Chow, 2001). This latter can be reverted to tocopherol by such physiological reductants as ascorbate and glutathione. Some of the radical is oxidized further to a-tocopherol quinone, which can be converted to the hydro-quinone by an NADPH-dependent reductase found in the mitochondria and microsomes of hepatocytes (Hayashi et al., 1992). Also an NADPH-cytochrome P450 reductase can catalyse reduction of the quinone to the hydroquinone. Organelle-localized, side chain oxidation of the hydroquinone leads to a-tocopheronic acid that is conjugated and excreted in the urine.

Vitamin K

The natural vitamin K group is comprised of phylloquinone (K1) of plants and menaquinone-7 (K2) and other bacterial and animal mena-quinones in which the number of isoprenoid units of the side chain varies. The synthetic compound that has the fundamental 2-methyl-1,4-naphthoquinone structure common to all the K group is menadione (K3); most commercial forms of K are water-soluble derivatives of this (Suttie, 2001). Absorption of natural K in the intestine generally is similar to that for other lipid and lipid-soluble components of the diet that are incorporated into mixed micelles. In the enterocytes, phylloquinone is packaged in chylomicrons, which exit to the lymphatic system. The tissue distribution of phylloquinone and menadione is significantly different with time. Menadione spreads over the whole body faster than phylloquinone, but the amount retained in tissue is low. Phylloquinone is found in the liver of those species ingesting plant material. Menaquinones containing 6—13 isoprenyl units in the alkyl chain occur in the liver of most species. Human liver reflects a K content of approximately 10% phylloquinone with a broad mixture of menaquinones (Matschiner, 1971). The menaquinones are absent in neonatal liver (Shearer et al., 1988), but the level rises with age of the infant (Kayata et al., 1989). In addition to liver, vitamin K concentrates in the adrenal glands, lungs, bone marrow, kidneys and lymph nodes.

Intracellularly, phylloquinone concentrates in the Golgi fraction and the microsomal fraction representative of the smooth endoplasmic reticulum

(Nyquist et al., 1971). Menaquinones (specifically MK-9) preferentially localize in mitochondria (Reedstrom and Suttie, 1995). There is preliminary evidence that a K-binding cytosolic protein may facilitate intraorganelle movement of the vitamin (Kight et al., 1995). As a deficiency develops, vitamin K is lost more rapidly from the cytosol than the membrane fractions (Knauer et al., 1976).

Metabolic alterations and utilization of vitamin K occur in organelle membranes, especially in the endoplasmic reticulum. Animal tissue cannot synthesize the naphthoquinone ring, but mena-dione, when incubated with liver homogenates, undergoes side chain addition at position 3 to form menaquinone-4 (Martius, 1961). This activity resides in the microsomes (Dialameh etal., 1970). In addition to such alkylation ofmenadione to form a menaquinone, the 3-phytyl chain of phylloquinone can be dealkylated and then realkylated to form menaquinone-4 (Thijssen and Drittij-Reijnders, 1994). Among liver metabolites of K, recognition of its 2,3-epoxide (Matschiner et al., 1970) was an important step in understanding what is now recognized as the K cycle, which involves the K-dependent carboxylase (Suttie, 2001). The scheme of connected events localized to the microsomal fraction are shown in Fig. 4.1, which underscores the function of vitamin K in the formation of g-carboxyglutamyl (Gla) residues from glutamyl (Glu) residues in certain proteins.

Reduction of the usual quinone forms of vitamin K is by microsomal K quinone reductases that are pyridine nucleotide dependent, and by a dithiol-dependent reductase that is sensitive to the anticoagulant, warfarin. This latter reductase appears to be the same as the activity that is the K

Vitamin Kquinone

—►Vitamin K hydroquinone

Disulphide

Disulphide

Disulphide

Disulphide

Dithiol

Reductases q2, C02

Carboxylase

— Glu protein Gla protein

Vitamin K epoxide

Fig. 4.1. The vitamin K cycle involved in formation of y-carboxyglutamyl (Gla) residues.

epoxide reductase (Gardill and Suttie, 1990). It has been suggested that the thioredoxin/thioredoxin reductase system is the physiologically relevant dithiol/disulphide system involved (van Haarlem et al, 1987; Silverman and Nandi, 1988). The carboxylase step, first shown to form Gla residues in prothrombin synthesis (Esmon et al., 1975), is in the lumenal side of the rough endoplasmic reticulum (Carlisle and Suttie, 1980) and utilizes CO2 and O2. The human enzyme has been purified (Wu et al., 1991a) with cloning and expression of its cDNA (Wu etal., 1991b). The chemical mechanism by which the K-dependent carboxylase proceeds has been propounded by Dowd et al. (1995). This involves addition of O2 to the K hydroquinone anion to form a dioxetane that generates an alkoxide. This latter is postulated to be the strong base necessary to abstract a hydrogen from the g-methylene group of a Glu residue. The vitamin K-dependent carboxylations are found not only in liver where blood clotting factors such as prothrombin are formed but also in skeletal tissues where mineralizations result as a consequence of the Ca2+-binding propensity of the Gla residues in proteins such as osteocalcin. Other Gla-containing proteins have been reported for other tissues, e.g. kidney (Griep and Friedman, 1980) and spermatozoa (Soute et al., 1985).

Thiamine (B1)

As with most water-soluble vitamins, thiamine enters epithelial cells by two mechanisms, i.e. active or carrier-mediated uptake and passive diffusion (Bowman et al., 1989). Below 2 ||M, thiamine is absorbed into enterocytes, mainly in jejunal and ileal portions of the small intestine, by a carrier-mediated process that is not dependent on ATPase (Tanpaichitr, 2001). It is unclear at present what the nature of the carrier is; however, there is a report of a thiamine-binding protein within liver and chicken egg white and yolk (Muniyappa et al., 1978). The entry of thiamine into most mammalian cells is a tandem process that is also linked with pyrophosphorylation (Rindi and Laforenza, 1997), a process that requires cytosolic thiamine pyrophosphokinase with ATP and Mg2+. A high percentage of the thi-amine in epithelial cells is (pyro)phosphorylated, whereas the thiamine arriving on the serosal side of the mucosa is largely free. Exit of thiamine from the serosal side is dependent on Na+ and the normal function of ATPase at the serosal pole of the cell. Upon vectoring of thiamine through the blood, much as thiamine pyrophosphate (TPP) within erythrocytes, about half of the total thia-mine is distributed in the skeletal muscles, with most of the rest in heart, liver, kidneys, and in brain and spinal cord, which have about twice the content of peripheral nerves. Leukocytes have a tenfold higher thiamine concentration than eryth-rocytes. Of the total body thiamine (~30 mg), about 80% is TPP, 10% the triphosphate (TTP) and the remainder the monophosphate (TMP) and thiamine. The three tissue enzymes known to participate in the formation of the phosphate esters are thiamine pyrophosphokinase responsible for TPP, TPP-ATP phosphoryltransferase, which catalyses the formation of TTP, and thiamine pyrophosphatase, which hydrolyses TPP to form TMP (Tanphaichitr, 2001).

Within mammalian cells, the operating coenzymic form of thiamine is TPP, which functions as the prosthetic group in two types of enzymic systems. One is cytosolic transketolase, important in the pentose phosphate pathway where reversible transketolations are catalysed between D-xylulose 5-phosphate and D-ribose 5-phosphate to form D-sedoheptulose 7-phosphate and D-glyceraldehyde 3-phosphate, or between D-xylulose 5-phosphate and D-erythrose 4-phosphate to form D-fructose 6-phosphate and D-glyceraldehyde 3-phosphate. The second type of coenzymic role of TPP is in the a-keto acid decar-boxylase subunits of mitochondrial multienzymic dehydrogenase complexes that convert pyruvate to acetyl-CoA, a-ketoglutarate to succinyl-CoA, and branched chain amino acids to their several metabolites. In the dynamics ofsuch multienzymic complexes, the a-keto acid substrate is decarboxy-lated and transferred via an a-hydroxyalkyl-TPP to the dihydrolipoyl moiety of a transacylase core. An acyl-CoA product is then released, and the oxidized lipoyl group is reduced by an FAD-dependent dehydrogenase that is linked to NAD+ in the mitochondrion.

The numerous urinary catabolites of thiamine reflect the considerable cellular degradative events, which include thiaminase-catalysed cleavage of pyrimidine and thiazole portions of the vitamin, alcohol dehydrogenase-catalysed oxidation of the b-hydroxyethyl group on the thiazole, etc.

(McCormick, 1988). Loss of the vitamin and its acid metabolites is relatively rapid. There is a high turnover rate ofabout 2 weeks, and little storage for any period of time in any tissue.

Riboflavin (B2)

Riboflavin, released from most of the dietary flavoproteins by dissociation followed by alkaline phosphatase and pyrophosphatase activities within the small intestinal lumen, enters the enterocytes where it is trapped metabolically by phosphorylation catalysed by flavokinase (McCormick, 1999; Rivlin and Pinto, 2001). Much of the riboflavin 5'-phosphate (FMN) so formed is converted further to FAD, and both flavocoenzymes function in metabolic processes. Upon exit at the serosal side of the lumen, ribofla-vin is complexed to both high- and low-affinity proteins (Whitehouse et al., 1991) for transport to the various cells of the body. Within most cells, the cytosolic flavokinase and FAD synthetase sequentially form the flavocoenzymes FMN and FAD, respectively. These ATP-utilizing enzymes, first purified from liver, are optimal with Zn2+ in the case of kinase (Merrill and McCormick, 1980) and with Mg2+ in the case of synthetase (Oka and McCormick, 1987). There are phosphatases that act on FMN and an FAD pyrophosphatase, but these hydrolytic enzymes are membrane separated and involved in turnover and release of the vitamin from the cell (McCormick, 1975). Flavocoenzyme biosynthesis is influenced by thyroid hormone (Rivlin, 1970; Lee and McCormick, 1985).

A small but important fraction of FAD is covalently bound to apoproteins within organelle membranes (Yagi et al., 1976; Addison and McCormick, 1978). Humans and other mammals have succinate dehydrogenase in the inner mito-chondrial membrane, and sarcosine and dimethyl-glycine dehydrogenases in the mitochondrial matrix. In these enzymes, FAD is attached through its 8a-position to an imidazole N of a histidyl residue. Monoamine oxidase in the outer mito-chondrial membrane contains 8a-(S-cysteinyl) FAD. In mammals capable of biosynthesizing vitamin C, L-gulonolactone oxidase, which has an 8a-(N1-histidyl)FAD, is found in the micro-somes, particularly in liver and kidneys. There are numerous non-covalent flavocoenzyme-dependent enzymes, some in the cytosol and some in the organelles. Examples include the FMN-dependent pyridoxine (pyridoxamine) 5'-phosphate oxidase of cytosol, the FAD-dependent fatty acyl-CoA dehydrogenase of the ß-oxidative system ofthe mitochondrial matrix, and the micro-somal NADPH-cytochrome P450 reductase that contains both FMN and FAD. The predominant flavocoenzyme within cells is FAD, which may constitute about 90% of the total flavin. Only approximately 5% of this becomes covalently bound to pre-formed apoenzymes as 8a-linked FAD.

The numerous urinary flavins reflect the extensive catabolism of side chain and ring methyl functions as well as dermal photochemical and intestinal microbial cleavage of the D-ribityl chain (McCormick, 1999). Among those catabolites that arise as a result of cellular oxidative actions are 7- and 8-hydroxymethyl (7a- and 8a-hydroxy) riboflavins, 10-formyl and 10-ß-hydroxyethyl flavins, lumiflavin and lumichrome (Chastain and McCormick, 1991).

Niacin

Both forms of niacin (nicotinic acid and nicotinamide) can be absorbed from the stomach, but more rapid and extensive absorption is from the small intestine (Kirkland and Rawling, 2001). For both vitamers, the uptake is facilitated as well as involving passive diffusion. In the enterocyte (and erythrocytes and other cells), nicotinic acid and nicotinamide are converted to NAD, the former through the Preiss-Handler pathway (Preiss and Handler, 1958) and the latter through the Dietrich pathway involving a nicotinamide pyrophosphorylase (Dietrich et al, 1966). The steps are shown in Fig. 4.2 and entail phospho-ribosyltransferases for nicotinic acid and nicotinamide, the nuclear adenylyltransferase for both nicotinic acid mononucleotide (NaMN) and nicotinamide mononucleotide (NMN), cytosolic NAD synthase, and the nicotinamide deamidase, which functions only at high concentrations of its substrate. The formation of NADP requires a cytosolic NAD kinase. Some nicotinic acid moves into the blood, as does nicotinamide, which is the principal circulating form released by NAD glycohydrolase activities important in controlling

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