Watersoluble vitamins and nonnutrients

Methylation ... 539

Thiamin 551

Riboflavin , 561

Niacin , 570

Folate 591

Vitamin B12 iT 603

Biotin 613

Pantothenate 619

Queuine * 625

Biopterin 628

Inositol 634



Hcys homocysteine

Met L-methiomne

MTHFR methylenetetrahydrofolate reductase (EC

MTR 5-methyl tetrahydrofolaie-homocysreine S-methyl transferase (EC2.1.1.13)

SAM S-adenosylmethionine

Metabolism is an integrated system of reactions that cannot be viewed from the aspect of just one component such as a particular nutrient. Silencing of gene expression by DNA methylation. which depends on an adequate supply of S-adenosylmethione (SAM), provides an illustration of the interdependence of methionine, folate, riboflavin, vitamin B6, vitamin BI2. choline, and other critical nutrients within a network of transporters, binding proteins, and enzymes. When intake of one nutrient is at the low end the outcome often depends on adequacy of the other nutrients as well as on individual metabolic disposition. Lack of a nutrient also can redirect the use of another nutrient and have indirect consequences in a seemingly distant metabolic network. Thus, weaknesses

HumJbiKjk of Nutrient ¡Vkltibolism Copyright C 2003 Elsevier l..ld

ISBN: 0-12-117762-X All njihts of reproduction in uny form reserv ed


S-Adenosyi methionine

S-Adenosy) homocysteine


Pyrldoxal $ phosphate

S-Adenosyi methionine


S-Adenosy) homocysteine dUMP

Homocysteine r


Pyrldoxal $ phosphate choline

Cysteine choline

Figure 10,t DNA mcihyl.ition depends on a web oFnutrienrs and metabolic events m one-carbon metabolism have broad consequences. I bey can cause cpigenetic disorders even bel'ore conception, birth defects during early pregnancy, slowed brain growth and cognitive development, anemia, cancer, diabetes, atherosclerosis, thrombosis, and other diseases. Obv iously, optimal nutrition is a complex goal that requires consideration of nutrient intake and health outcomes in a broad context.

SAM-de pen dent methylation

Oe novo creatine synthesis uses about 70% of the SAM available for methylation (Wyss and Kaddurah-Daouk. 2000). SAM is also the prerequisite precursor for the production ofthe polyamines spermine and spermidine. Much smaller amounts go to the synthesis of carnitine (0.3 mmol d). choline, estrogen, and other compounds. As the example of DNA methylation emphasizes, the quantity ofthe product does nol indicate the importance ofthe reaction,

Specific DNA target sequences are methylated by several DNA (eytosine-5-)-methy I transferase (EC2.1.1.37, zinc-binding) isoenzymes. The presence of a 5-methyl group on cytosine usually blocks transcription directly or through attached binding proteins. Current evidence indicates that silencing by selective methylation regulates developmental appropriate expression of genes and suppresses parasitic insertions, Hypomethylation of DNA due to suboptimal nutrient intake and metabolic disposition has been linked to an increased risk of cancer (Ehrlich, 2002). Cancer of colon, cer\ tx. breast, stomach, esophagus, and other sites occurs w ith increased frequency in people with low habitual intake of folate. It is likely that additional nutrients involved in one-carbon metabolism influence cancer risk, but this issue needs more investigation ( Ames. 2001}. Hypomethylation may also contribute to the deterioration of brain function with aging and other age-typical afflictions (Selhub. 2002).

Methylation of parental DNA imprints some genomic regions Faulty imprinting is linked to severe developmental defects in Willi Prader and Angelman syndromes (Nieboltsand Knepper, 2001) and possibly much more common adulthood conditions such as obesity and diabetes (Cooney el a!.. 2002).

Sources of methyl groups

While methyl groups abound in nutrients and their metabolites, only a few of them can be used for SAM-depcndent methylation. The major sources are methionine, choline, and 5-methyltetrahydrofolate (5mTHF).

Met intakes depend to a significant degree on dietary habits. Compared with meat eaters ovo-lacto-vegetarians have much lower (770 vs. 1450 mg.d) average intakes (Sachan ct ul.. 1997).

The second step of choline breakdown, catalv/ed by the zinc-enzyme betaine homocysteine methyl transferase (EC2.1.L5), remethylates homocysteine (Hcys) to Met and thus provides a methyl group for SAM synthesis. Since the tic novo synthesis of choline requires the SAM-mediated transfer of three methyl groups, only dietary choline can contribute to net SAM synthesis. Daily choline intakes have been estimated at 600 lOOOmg (Zeisel. 1994).

A much more significant pathway of Hcys remethylation is catalyzed by 5-methylteirahydro folate-homocysteine S-meihyltran si erase (MTR, EC2.1J.13). Very little of the necessary eosubslrate 5 mTHF is generated by direct methylation of THE such as in the betaine homocysteine methyltransterasc-eatalyzed reaction, but comes from the reduction of 5,10-methylene-THF by methyIenetetrahydrofolate reductase (MTHFR; 1(1. 5.1.20). Large quantities of this metabolite arise from the metabolism of serine (40mmoFd), glycine (I50mmold). histidine (17mmol/d), and formate. Both a low supply of folate and reduced MTflFR activity diminish the availability of the 5 mTHF cosubstrate for optimal Met recycling.

The active cob(l)al amine form of MTR becomes slowly oxidized to the inactive cob(II)alamine form. The FAD- and FMN-dependem methionine synthase reductase (LC2.I 1.135) can reactivate the cob(l)alanunc-containing form again by reductive methylation (Leclerc eta!.. 1998). t his reaction uses cytochrome b5. which in turn is regenerated by NADP1 ¡-dependent cytochrome P450 reductase (EC, another enzyme w ith both FAD and FMN as prosthetic groups (Chen and Banctjee, 1998). Inhalation of nitrous oxide irreversibly inactivates MTR (Home ct ul., 1989; Riedel etaL 1999).


Ames liN. DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Volution Res 2001;475:7 20 Chen Z. Banerjee R. Purification of soluble cytochrome h5 as a component of the reductive activation of porcine methionine synthase. J Biol Chew 1998:273:26248 55

Cooncy (A, Dave AA. Wolff GL. Maternal methyl supplements in mice all'ect ep i genetic variation and DNA methylation of offspring, J Nutr 2002:132:2393S-24(X)S Ihrhch VI. DNA methylation, cancer, the immunodeficiency,centromeric region insiabil-ity, facial anomalies syndrome and chromosomal rearrangements, J Nutr 2002: 132:2424S 2429S

Home DW, Patterson I). Cook RJ. Effect of nitrous oxide inactivation of vitamin 1312-dependent methionine synthetase on the subcellular distribution of folate coenzymes in rat liver Arch Biochem Biophys 1989:270:729 33 Leclerc l>. Wilson A, Dumas R. Gafuik t . Song D, Watkins D, Heng HH. Rommens JM. Scherer SW Rosenblatt ÜS, Gravel RA. Cloning and mapping of a cDNA for methionine synthase reductase, a tlavoprotein defective in patients \\ ith homocystin-uria. Pmc Natl Acad Sri USA 1998;95:3059-64 Nicholls RD. Ktiepper JL. Genome organization, function, and imprinting in Prader W illi and Angelman syndromes. Ann Rev Gen Human Gen 2001:2:153 75 Rtedel B. Fiskerstrand T. Refsutn H. Ueland PM. Co-ordinate variations in methyl-nialonyl-CoA mutase and methionine synthase, and the cobalaminee cofactors in human glioma cells during nitrous oxide exposure and the subsequent recovery phase. Biochem./ 1999:341; 133-8 Sachan DS. Daily JW III. Munroe S(i. Beauchene RE. Vegetarian elderly women may risk compromised carnitine status. 1'eg Nutr 1997; 1:64 9 Selhub .1. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Sutr Hhh Aging 2002;6:39-42

Wyss M, Kaddurah-Daouk R Creatine and creatinine metabolism, Physiol Rev 2000; 1107 -213

Zeisel SI I. Choline. In Shils ME, Olson JA. Shike M.eds. Modern Nutrition in Health and Disease. Lea & Febiger. Philadelphia. 1994. pp.449-58

The hexurontc lactone L.-ascorbic acid is a water-soluble essential nutrient (ascorbate. L-xvloascorbic acid antiscorbutic factor, antiscorbutic v itamin. I -3-ketothrcohexuronic

Vitamin C

L-Ascortjic acid

Semidehydroascorbate (SDA)

Dehydroascorbate (DHA)

Figur» 10.Z Vitamin C has three different redo* states acid, 3-oxo-L-gulofuranolactone[enol form] molecular weight 176). Vitamin C occurs in three different redox states: Fully reduced as ascorbatc (ASC), partially oxidized as semidehydroascorbate (SDA), and fully oxidized as dehydro-L-ascorbic acid (DHA). Several derivatives are also biologically active.


ASC L-ascorbic acid (specifically to indicate the reduced form)

A2S ascorbate-2-sulfate

DHA dehydro-L-ascorbic acid

CLUT1 glucose transporter 1

PAPS 3'-phosphoadenosine 5'-phosphosulfate

SDA semidehydroascorbate

SGLT1 sodium-glucose cotransporter

SVCT1 sodiutn-ascorbace transporter 1 (SLC23A2)

5VCT2 sodium-ascorbare transporter 2 (5LC23A1 )

Nutritional summary

Function: Vitamin C is essential for gums, arteries, other soft tissues, and bone (collagen synthesis), for brain and nerve function (neurotransmitter and hormone synthesis), for nutrient metabolism {especially iron, protein, and fat), and for antioxidant defense (directly and by reactivating vitamin E) against free radicals (free radicals increase the risk of cancer and cardiovascular disease).

Food sources; Many fruits and vegetables provide at least 20% of the recommended daily intake per serving; citrus fruits, berries, and tomatoes are especially rich sources. Prolonged storage, extensive processing, and overcooking greatly diminish vitamin C content of foods.

Requirements Adult women should get at least 75nigday, men at least 90mg/day i Food and Nutrition Board. Institute of Medicine, 2000). Age over 50, smoking, strenuous exercise, heal, infections, and injuries each may increase needs. Deficiency: Scurvy (symptoms include painful swelling and bleeding into gums, joints, and extremities, poor wound healing, fatigue, and confusion) has become rare in most countries; 10mg/day prevent it. Lower than optimal intake may diminish immune function and wound healing, and increase the risk of heart disease and cancer, especially in susceptible indiv ¡duals. If intakes are low. stores last only a few weeks.

Excessive intake: Daily doses of 2000mg or more may irritate stomach and bowels, cause kidney stones, and interfere v, ith copper status.

Endogenous sources

Unlike most other vertebrates, humans (just like all primates and guinea pigs) lack the enzyme for the linal step of ascorbatc synthesis (L-gulonolactone oxidase; ECl. i .3.X)

from hexose precursors due to multiple deletions and point mutations in the responsible gene. Thus, compounds with vitamin C activity have to be obtained from food.

Dietary sources

Foods contain a mixture of compounds with vitamin C activity: ASC (the reduced form), SDA (the partially oxidized form), DHA (the oxidized form), and small amounts of ascorbate-2-sulfate (A2S), Aeylated ASC, ascorby! phosphate and other derivatives are sometimes used as food additives. (Note: food tables usually report only the ASC content of food, not total bioactive vitamin C). ASC and SDA are oxidized rapidly when exposed to air without losing their biological activity for humans. All forms of vitamin C decompose during prolonged heating or storage of foods.

Typical intakes of vitamin C from food in the US arc 77mg day in women and 109mgday in men. The best food sources arc fruits and vegetables, especially citrus, berries, peppers, tomatoes, broccoli, greens. On average, a serving of fruits or vegetables provides about 30 rag v itamin C (Lykkesfeldt et al.. 2000). Consumption of nonfood sources is common, most often as multivitamin supplements, which usually prov ide 50 00 mg day. or as megadose preparations which may contain 5(H) mg or more.

Digestion and absorption

Small amounts of ingested ascorbate arc absorbed nearly completely, but fractional absorption rapidly drops to less than 20% when daily intakes are above 2(H) mg (Blanc hard et ul.. 1997). ASC and SDA may be oxidized in the lumen of the intestine, partially through the activity ofceruloplasmin {ECU6,3.11 DHA is taken up slightly more efficiently in the proximal than in the distal small intestine (Malo and Wilson, 2000) by facilitated transport via an unknow n mechanism. The glucose transporters that facilitate DHA transfer at other sites (GLUT1, GLUT3. and GLUT4) are nol sufficiently expressed at the luminal side to explain transport. GI.I IT2. GLUTS, and the sodium glucose cotransporler 1 do nol accept DHA (Liang et ul., 20011. ASC uptake, in contrast, is more efficient in the distal small intestine. The sodium-dependent ascorbate transporter I (SVCTI, SLC23A2) mediates its uptake with high efficiency and specificity (only the L-form of ASC is transferred). Two sodium ions arc needed for the transport ofone ASC: one of these sodium ions may be actually coupled to the simultaneous transport of glucose via the sodium/glucose eotransporter (SGLT1, Malo and Wilson. 2000). Absorption is efficient, with a maximum around three hours after ingestion (Piotrovskij et al.. 1093). Ascorbate-2-sulfate (A2S) is not effectively hydrolyzed in the intestine and noi absorbed. Ascorbate-dependent glutathione reductase (EC and reduced glutathione (non-enzymically) in the eiUerocyte reduce DHA to ASC; the oxidized glutathione, in turn, is regenerated by a system of thioredoxin and NADPH-dependent thioredoxin reductase (EC The high intracellular concentration generates enough of a gradient to drive ASC via the sodium-ascorbate transporter 2 (SVCT2. SLC23A11 across the basolateral membrane (Rose and Wilson. 1097: Liang et al., 2001).

2 Na

Intestinal turnen

2 Na

Intestinal turnen

Brush border membrane

Figure 1(1.3 lmrsrin.il up!.¡te ufvii.imin C

Basolateral membrane

Capillary lumen

Brush border membrane

Figure 1(1.3 lmrsrin.il up!.¡te ufvii.imin C

Basolateral membrane

Capillary endothelium

The colon might also have some absorptive capacity, since both sodium ascorbate transporters are expressed there.

Transport and cellular uptake

Blood circulation: ASC, the main form in blood (l>5%). is transferred from blood to some tissues (chromaffin cells, osteoblasts, fibroblasts) predominantly by the two sodium-dependent ascorbate transporters (SVCTI and SVCT2) in an energy-dependent, concentrâtive process. SVCT1 is expressed in most tissues, while the expression of SVCT2 is not expressed in skeletal muscle and lung.

On the basis of recent observations in erythrocytes the existence of an NADll-dependent, reducing DHA transmembrane transporter has been proposed (Himmelreich et a!.. 1998). If the same transporter system were present in enterocytes this would provide another explanation for the near absence of Dl IA in blood. Blood brain barrier: ASC in interstitial tluids is oxidized (by ceruloplasmin, iron compounds, or other agents) to DHA which is then transferred via glucose transporters (GLl/Tl, GLUT3, and QLUT4) into (and out of) cells (Liang et al.. 2001). Reduction of DHA to ASC blocks reverse transport, since the t «LUI s are impervious to ASC and SDA; the sodium.ascorbate cotransporter 2 (SLC23A I. distinct from the ubiquitous SVC IT I completes the concentrâti\e transport into brain. This mechanism may explain the ten-fold higher concentration of ASC in brain compared to blood.

Muterno fetal transfer: Similar to the arrangement in the small intestines. DHA transport into the syntrophoblast uses glucose transporters, while ASC is taken up via SVC'T I DHA can be reduced inside the syntrophoblast layer. ASC is then exported to the fetal side via SVCT2.


DHA is reduced to ASC in cytosol by ascorbate-dependcnt glutathione reductase (ECI.8.5,1), NADH-dependent monodehydroascorbic acid reductase (EC1.6.5.4). the NADPH-dependent selenoenzyme thioredoxin reductase (EC1.6.4.5). or nonenzyme ica lly by reduced glutathione (since this is a near-equilibrium reaction. ASC can also reduce oxidized glutathione). SDA, which is the unstable radical intermediate generated by some reactions, is reduced by NADH-dependent monodehy-droascorbate reductase iK and by thioredoxin reductase (EC1.6.4.5) (May etal., IWH); another important mechanism may be the NADH-dependem DHA-reducing transporter found in erythrocytes. Additional DHA and SDA-reducing enzymes, including NADPI(-dependent DMA-reductase. have been described, but are not fully characterized, yet.



thioredoxin. thioredoxin. oxidized reduced thioredoxin. thioredoxin. oxidized reduced



Figure 10.4 Intracellular metabolism of vitamin C

L-asccrb ate-cytochrome-b5 reductase (ECl,10.2.1> catalyzes the shuttling of reducing equivalents w ith cytochrome b5M across the phospholipid bilayer enveloping microsomes, neurovesicles, and chromaffin granules, thereby coupling the oxidation of ASC to SDA inside to the reduction of SDA to ASC outside.

A small amount of available ASC is converted by alcohol sulfotransferasc (EC2.H.2.2) into A2S using 3'-phosphoadenosine 5'-phosphosulfate (PAPS) as the cosubstrate; this enzyme is otherw ise important for the conjugation ofa wide range of steroids (e.g. dehydroepiandrosteronc), bile acids, and drugs in the adrenals and liver.

Figure 10.5 Vnamin C redo* equivalents are shun led across the miiochondrial membrane

H2S04 H,0

Ascot bate Ascorbate 2-suit ate

1 Alcohol sulfotransterase

2 Arylsultatases A and B

F igure 10.6 Ascorbate 2-sulfate metabolism

Dehydroaseorbate (OH A)

Dehydroaseorbate (OH A)

Figur* 10.7 Non-en/ymic degradation of vitamin C






Oxalate h<A>

ASC is released again when A2S is hydrolyzed by arylsulfatase A (KC3.1.6.8)oraryl-sulfatase 13 [EC3.1.6.12).

DMA in blood is broken down rapidly and irreversibly by non-enzymic hydrolysis to 2.3-ketoguIonate, sonic of which is hydrolyzed further to oxalate and L-threonate. The extent of this degradation is proportional to DHA concentration. Increased amounts are lost by tobacco smokers due to accelerated ASC oxidation upon exposure to free oxygen radicals (Lykkesfeldt et <il.. 2000).


The highest total ascorbate tissue concentrations are in leukocytes, adrenal glands, pituitary, and brain. Replete body stores are in the range of I 2 g. depending on habitual intakes. Stores below 300 mg are thought to cause the development of severe deficiency symptoms (scurvy). The highest concentrations of bioactive metabolites arc in adrenal and pituitary glands, corpus luteum. brain, liver, pancreas, and spleen. About 3% of total body pool turns over per day. Biological half-life of stored ascorbate increases with depletion; it ranges from S to 40 days (Kallner et ul,. 1979). A2S may have special importance for the storage of ASC.


Information is lacking on mechanisms that maintain the body's stores of the various ascorbate metabolites. Follicle-stimulating hormone (fSII) and IGF-I induce the transport into follicular granulosa cclls of ASC via ascorbate transporter and of DHA via GLUT I. Luteinizing hormone {LID and PGF2a stimulate the energy- and sodium-dependent efllux of ASC from luteal cells. The role of hormonal regulation of ASC and D11A transport in other tissues is unclear.


ASC, SDA, DHA. 2,3-ketogi11 o nate. and other catabolic products pass completely into primary glomerular filtrate, owing to their small size. ASC is reabsorbed from renal tubules by the (electrogenic) sodium-dependent ascorbate transporter. Nearly alt ingested vitamin C is eventually excreted with urine as ASC., 2,3-ketogulonatc, or oxalate. Usually, losses with other body fluids or feces are not significant.


Free radical scavenging: Free radicals are highly reactive chemicals with at least one Unpaired electron. They are generated in the course of normal biological functions, particularly from oxidation reactions in the mitochondria and from the activity of white blood cells. Ascorbate in its various redox states comprises a particularly versatile free radical scavenging system in the aqueous phase, since either one or two electrons can be accepted. ASC is particularly effective in quenching the hydroxy! radical, The resulting oxidi/ed forms (ascorbyl radical, SDA) are reduced again to ASC by the enzyme systems described above. ASC is essential lor the non-enzymic reactivation of toeopheryl quinone, the product of the reaction of alpha-tocopherol with an oxygen free radical. ASC also protects folate and other compounds that are highly susceptible to oxidation. While ASC is an antioxidant under most circumstances, it is important to point to the pro-oxidant potential of ASC w hen promoting iron-catalyzed reactions. ASC can reduce iron that has been oxidized in a Fenton type reaction (U >< )l I +■ Fc*' -> LO+OH + Fe1'; or IUOj + Fe2' -»OH+OH + Fe1' 1; this iron recycling reaction I Fe1' + ASC —► Fe2' + SDA 1 can perpetuate the generation of oxygen free radicals.

Protein modification: Ascorbate maintains the reduced form of iron in two types of metalloenzymes that post-translationally hydroxylatc lysine and proline residues in collagen (EC 1.14.11,2 procollagen-proline. 2-o.xoglutarate-dioxygenase and EC1.I4.11,4 procollagen-lysine. 5-dioxygenase: the latter activity is exerted by two genetically distinct isoenzymes). Each reduction of l ei 111) to Fe|lh oxidizes one ASC to SDA. Another ascorbate-dependcnt copper enzyme (EC1.I4,17.3 pcptidyl-glycine alpha-amidating monooxygenase) activates numerous protcohormones (including 1RH, CRF, GnRH. neuropeptide V. endorphins, gastrin, pancreatic polypetide, atrial natriuretic factor, and arginme \asopressin) in neurosecretory vesicles: each modific reaction oxidizes one ASC molecule to Dl 1 A,

Amino acid metabolism: ASC participates in the metabolism of phenylalanine and tyrosine, and the synthesis of carnitine, ASC is one of sev eral alternative reductants for the synthesis of homogentisinate, an intermediary metabolite of pheny (alanine and tyrosine catabohsm. by 4-hydroxypheny[pyruvate dioxygenase (EC1.13.11.27). For the following hydroxylationof homogentisate. ASC is again necessary to maintain the ferrous slate of enzyme-bound iron in homogentisate 1 ^-dioxygenase (EC

In a similar way. ASC keeps the copper of dopamme-bcta-monooxygenasc (EC1.14,17,1) in its reduced state, thereby ensuring synthesis of noradrenaline (norepinephrine) from dopamine. At least two steps of carnitine synthesis from lysine are mediated by ASC-de pen dent ferroenzymes. Trimethyllysine is hydroxy lated by trimethy I lysine dioxygenase (EC1.14.11.8), and the ultimate precursor, trimethy lam-moniobutanoate, is converted into carnitine by gamma-butyrobetaine hydroxylase (ECU4.M.1),

Steroids and lipids: ASC is important for the last three steps of aldosterone synthesis, II beta- and 18-hydroxylation (EC1.14.15.4 steroid 11 -beia-monooxygenase and EC 1.14.15,5 eorticosterone 18-tnonooxygcnase) and oxidation of 11-deoxycorticosterone, m the adrenal cortex. All three reactions are mediated by cytochrome P-450scc, the activity of which decreases with decreasing availability of ASC. The same is true for another cytochrome, CYP11B2, which mediates cholesterol 7-alpha-hydroxv 1 ation in liver microsomes, a key step of bile acid synthesis. The mechanism and stoichiomeirv of ASC in these reactions is not well characterized. Cytochromes generate profuse amounts of oxygen free radicals, and it has been suggested that ASC is essential to protect the enzyme protein and the lipids in the surrounding microsomal membrane.

In a reaction catalyzed by 1.-ascorbate cytochrome-b5 reductase (EC ASC generates the reducing equivalents (ferrocytochromc b5> for the desatnration of fatty acids in microsomes.

ASC can provide, as an alternative to NADP11, reducing equivalents for the hydroxylation of N-acety I neuraminic acid (EC CM P-N-aceiylneuraminate monooxygenasc), a critical step in the synthesis of GM3(NeuGc) gangliosidcs in many tissues.

Iron metabolism; ASC enhances absorption of non-heme iron from the small intestine. Generally, it has been assumed this is due to a reduction of ferric iron by ASC. but this mechanism has been disputed. ASC is also necessary for the mobilization of ferritin iron deposits. It is able to penetrate through molecular pores of the ferritin-Fc(lll) complex, where it reduces iron: the resulting ejection of f'e(II) from the crystal lattice makes iron available for binding lo transferrin and transport away from storage sites, l or each mobilized iron one ASC is oxidized to DHA. Sulfate transfer: A2S appears to be a reservoir of sulfate groups which become available when A2S is hydrolyzed by arylsulfatase A (EC3.1.6.8) or arylsulfatase B (EC3.1.f>. 12). This may explain how A2S promotes the sulfation of cholesterol, and of glucosaminoglycans such as chondroilin and dermatan sulfate.

Since the activities of both arylsulfatase A or arylsulfatase B are inhibited by ASC. replete vitamin C status not only slows the release of ASC from A2S. but also the hydrolytic release of noradrenaline and a wide range of other sulfoconjugated compounds.

Other functions: Dietary ASC in the stomach suppresses the reaction of ingested nitrites \vith food proteins to nitrosamines and thereby decreases carcinogen exposure (Helser et ul., 1992). ASC also has been reported to directly inhibit the growth of some lumor cell lines in vitro.

ASC can reduce various elements, such as chromium, and thereby affect their bioavailability and biological activity. It has been proposed that ASC reduces selenile to elemental Sc which then can form links with selenocysteine in proteins. The biological significance of such an effect is not known.

ASC has also been suggested to act as an aldose reductase thereby diminishing the risk of free radical production from sorbitol in diabetics (Crabbe and Goode. 1998),

ASC is also a reducing agent for enzymes involved in prostaglandin synthesis (Horrobin, 1996), the mixed-function oxidases, and the cytochrome p450 electron transport system (Tsao. 1997) contributing to the metabolism of xenobiotics.


8 Ian chard J, TozerTN, Rowland VI Pharmacokinetic perspectives on megadoses of ascorbic acid. Am J Clin Nutr I997;66:l 165 -71 Crabbe MJ, Goode I). Aldose reductase: a window to the treatment of diabetic complications? Pmgr Ret Eye Res I99K; 17:313- 83 Food and Nutrition Board. Institute of Medicine, Dietary Reference Intakes for vitamin C.

vitamin P. selenium, and carotcnoids. National Academy Press. Washington, DC, 2001J llelser MA, Hotchkiss JH, Roe DA. Influence of fruit and vegetable juices on the endogenous formation of N-niirosoprolinc and N-nitrosotliiazolidine-4-carboxyIic acid in humans on controlled diets. Carcinogenesis 1992:13:2277- SO Himmelreieh U. Drew K\. Serianni AS. Kuchel PW 13C NMR studies of vitamin C

transport and its redox cycling in human erythrocytes. Biochem 1998:37:7578-8 Horrobin DF. Ascorbic acid and prostaglandin synthesis. Suhcell Biochem 1996;25:109-15 Kallner A. Hartmann D. Hornig D. Steady-state turnover and body pool of ascorbic acid in man. Am J Clin Nuir 1979;32:530-9 Liang \VJ, Johnson D, Jan is SM. Vitamin C transport systems of mammalian cells. Mnl

Membrane BioI 2001; 18:87 95 Lykkesfeldt J. Christen S. W4I lock LM, Chang HH, Jacob RA, Ames BN. Ascorbate is depleted by smoking and rcpletcd by moderate supplementation: a study in male smokers and nonsmokers w ith matched dietary antioxidant intakes. Am J Clin Nutr 2000:71:530 6

Malo C. Wilson J\. Glucose modulates vitamin C transport in adult human small itites-

tinal brush border membrane vesicles. J Nutr 2000;130:63-9 May JM. Cobb CE, Mendiratta S. Hill KE, Burk RF. Reduction of the ascorbyl free radical to ascorbate by thiorcdoxin reductase. J Biol Chan 1998:273:23039 -15 Piotrovskij VK, Kallav 7., Gajdos M. Gerykova M. Trnovee T. The use of a nonlinear absorption model in the study of ascorbic acid bioavailability in man. Biopharm Drug Disp 1993:14:429 42 Rose RC. Wilson JX. Ascorbate membrane transport properties. In L Packer, J Fuchs, cds.

Vitamin C in Health anil Disease Marcel Dekker. New York. N.Y, 1997, pp. 143-62 Tsao CS. An overview of ascorbic acid chemistry and biochemistry lit Packer I .. Fuchs J, eds. Vitamin C in Health and Disease. Marcel Dekker, New York, NY, 1997. pp.25 58

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