Vitamin A

The term vitamin A usually refers to retino! I vitamin Al, 3,7-di methy 1-9(2,6,6-trimethyl-I -cyclohexen-1 -yl)-2,4.6.8-nonatetraen-1 -ol, obsolete name ophthalamin; molecular weight 2861, its esters, and the metabolically equivalent retinal (retinaldehyde. retinene, vitamin A aldehyde, axerophthal: molecular weight 284). Beta-carotene, alpha-carotene.

Atl-trans-retinol

Atl-trans-retinol

L I AII-trans-retinal

Figure 9.3 Several structurally related compounds have vitamin A activity cryptoxanthin, and a few other carotenotds, which can be metabolieally converted into retinal and retinol, are referred to as provitamin A. The term vitamin A should not be used for retinoic acid (vitamin A acid, 3,7-dimeihyI-9-(2,6.6-trimethyl-1 -cyclohcxen-1 -y I )-2,4,6,8-nonatctiaenoic acid tretinoin; molecular weight 300), a metabolite of retinol with important biological functions, because it cannot be converted back into its precursor.

Abbreviations

ADH alcohol dehydrogenase (EC! .1.1.1)

CRBP2 cellular retinol binding protein 2, RBP2

LDH lactate dehydrogenase isoform (EC 1.1.1.27)

RAE retinol activity equivalents

RALDH1 retinal dehydrogenase 1 (EC1.2.1.36)

RALDH2 retinal dehydrogenase 2 (EC1.2.1.36)

RBP1 retinol-binding protein 1 (cellular RBP}

RBP2 retinol-bindtng protein 2 (cellular RBP of enterocytes)

RBP3 retinol-bindtng protein 3 (interstitial RBP)

RBP4 recinol-binding protein 4 (in btood)

vitA vitamin A (all forms)

Nutritional summary

Function: Vitamin A (vitA) is essential for vision, immune function, and regulation of cell growth.

Food sources: Only animal foods contain retinol. Particularly rich sources are liver, flesh foods, eggs, and fortified milk. Good sources of pro\ itamin A earotenoids are carrots, spinach, broccoli, yellow melons, mangos, and many other dark-green or orange-yellow colored fruits and vegetables. The activation of vitA requires riboflavin, niacin, zinc, and iron.

Requirements: To account for metabolic differences between \ tt A and its carotenoid precursors dietary amounts are expressed as equivalents of I jig retinol (retinol activity equivalent = RAE). I2pg beta-carotenc and 24p.g alpha-carotene or hela-cryptoxan-thin corresponds to 1 RAE. Adults should gel between 700 (women) and 900 (men) RAE. Women's needs are higher during lactation.

Deficient A lack ofvilA (for which about one-third of lite world population is at risk! initially causes reversible night blindness, later increasingly severe and irreversible loss of vision due to changes of the eye structure (xerophthalmia with drying of the conjunctiva and increasing opacity of the corneal. Hyperkeratosis and other skin lesions are further typical effects of inadequate intake. Another concern with even mild deficiency is impaired immune function, especially in children. Excessive intake: Retinol intake above I000p.g/d increases bone fracture risk in older people. Moderately high intakes of retinol (3000p.g/d). but not of provitamin A earotenoids. during early pregnancy increase the risk of birth defects. Daily ingestion of 15000 pg retinol initially may lead to itching, scaling of skin, malaise, and loss of appetite. Cerebrospinal pressure may increase causing nausea, vomiting, headaches, and eventually seizures, coma, respiratory failure, and death.

Endogenous synthesis

Beta-carotene 15,15'-dioxygenase (EC 1.14.99.36) in the cytosol of mature jejunal enterocytes, liver, kidney, and testes splits earotenoids in the middle (Duszka etui.. 1996: Barua and Olson, 2000). This enzyme, which is actually a monooxygenase, requires bile acids and iron for its three-step activity (cpoxidation at llie 15.15'-double bond

Beta-carotene

Beta-carotene

1515-dioxygenase (bile acids, iron)

1515-dioxygenase (bile acids, iron)

Alcohol { 2 NADH

dehydrogenase

Figure 9.4 Seta-carotene and a few other earotenoids can be converted into retinol

Figure 9.4 Seta-carotene and a few other earotenoids can be converted into retinol hydration to the diol, and oxidatho cleavage). The provitamin A carotenotds yield two (beta-carotene) or one (alpha-carotene, gamma-carotene, beta-cryptoxanthin. beta-/eaearotene) retinal molecules (Rock, 1997). Some other carotenoids are also cleaved (e.g. lycopene, lutein, and zeaxamhin), but do not generate a fragment that can be convened into retinoU

Excentric( asymmetric) cleavage at the 14', 13' double (Dmitrovsk Wet a!.. 1947) or the 9'. 10' double bond( Kiefcrf/ al., 2001) by as yet incompletely characterized enzymes appears to play a much smaller role. Excentric cleavage products include N'-/j-apnea ro tonal (the largest metabolite), H)'-y3-apocarotenal. 12'-£f-apocarotenal. and 14'-fi-apocarotenal. Oxygen free radicals, such as fatty acid hydroperoxides, can also react with any of the conjugated polyene double bonds and initiate cleavage (Yeum et uL. 1995). The antioxidant alpha-tocopherol can prevent such random cleavage and keep retinal yieid near the theoretical optimum (Yeum et al.. 2()tH>). The side chain of longer fragments can be shortened by beta-carotene 15,15'-¿¡oxygenase to generate retinal (Paik et al.. 2001).

Retinal resulting from carotenoid cleavage is rapidly metabolized mainly to retinol. A specific lactate dehydrogenase isoform (LDH-C, ECl. 1.1.27) in testes is closely associated with beta-carotene 15.15'-dioxygenase, and the reduction of newly generated retinal may be its main physiological function (Paik et al.. 2001). In most other tissues class III alcohol dehydrogenase (ADM, ECl.1.1.1) may be more important

Alpha-carotene

Alpha-carotene

Cryptoxanthin

Cryptoxanthin

Figure 9,5 Carotenoids that can be convened into retinol

Figure 9,5 Carotenoids that can be convened into retinol

I Molotkov et«£, 2002). Retinoic acid is exported trough an unknown pathway into portal blood and taken up by the liver.

Dietary intake

Foods contain retinol, retinyl esters, provitamin A carotenoids, and also compounds with a restricted spectrum of vitamin A activity, such as retinoicacid. Several isomeric forms of both retinol derivatives and carotenoids are possible. The most common form of retinol in natural foods is the all-trans isomer. Much smaller amounts of 9-cis-relinol and other v itA metabolites are ingested with some foods. Synthetic retinol may also contain isomers in addition to the biologically active all-trans-retiuol.

Compounds with vitA activity are very sensitive to oxidation, isomeri/ation. and polymerization

To facilitate assessment, intakes of different forms of vitA are usually expressed as retinol activity equivalents (RAE) with I p.g all-tmns-retinol as the basis (Food and Nutrition Board Institute of Medicine, 2002). The conversion factors for non-retinol compounds take bioavailability and metabolic yield into account. Thus, I2(ig of ingested beta-carotene corresponds to 1 RAE. as do 24 ¡eg of alpha-carotene and 24 ji,g ofbeta-cryptoxanthm, International Units (IU) for retinol are divided by 3.33 to convert into RAE. those for ^-carotene are div sded b\ 20.

Retinol and directly related compounds arc only present m animal-derived foods. The highest concentration is in organ meats, such as beef liver (106 |ig RAE/g). Another group ofretinol-rich foods are hard and cream cheeses such as Swiss cheese (2.5 jig-'g). cheddar (2.8 p.g g). and regular cream cheese (3.8 p.g.g). Eggs contain about t >J p,g g. milk 0.6 |xg/g.

Good plant-derived sources of v itamin A precursor carotenoids are green leafy vegetables, including spinach (8.2 p.g RAE/g), kale (7.4mg/g>, chard (3.1 p.g g). and broccoli (1.4 M.g g). Other good sources are orange or red-colored vegetables and fruits, such as sweet potatoes (I6.4p.gg) and carrots (24.6 pgg).

Median daily intakes of vitA from all sources were estimated to be around 900 |jg for men. and around 700 jig for women in the US (Food and Nutrition Board Institute of Medicine, 2002; Appendix C). More than half of their total vitA intake comes from preformed retinol.

Digestion and intestinal absorption

Both retinol derivatives and carotenoids are absorbed from the proximal small intestine in a process that requires the formation of mixed micelles and concurrent fat absorption. About 70 90% of ingested retinol is absorbed (Sivakumar and Reddy, 1972), but only 3% or less of carotenoids (Edwards <.■/ ai., 2002).

Retinol; Re tiny I esters are cleaved by lipase (EC3.1.1.3) and sterol esterase (EC3.1.1.13) from pancreas and at least one other brush border esterase. Retinol is only absorbed efficiently when it is incorporated into mixed micelles along with lipase-digested fat (fatty acids and m onoglycen des), bile acids, and phospholipids (Harrison and Hussatn. 2001). It has been suggested that a specific transporter may be involved in retinol uptake, but its identity remains elusive. Rctinol-binding protein 2 (RBP2, cellular retinol

Diagram Xerophthalmia

Lymph duct

Intestinal lumen

Brush border membrane

Figure <i.b Intestinal absorption of vitamin A

Intestinal lumen

Lymph duct

Brush border membrane

Figure <i.b Intestinal absorption of vitamin A

binding protein 2. CRBP2) is needed for return! metabolism and trafficking across the enterocyte. For example, phosphatidylcholine-retinol O-acy I transferase (EC2,3.1.135) cstcrilies only retinol that is bound to RBP2. Rctinol and rctinylestcrs exit enterocytes as integral components of chylomicrons. The details of their transfer into chylomicrons are not yet understood. A small amount of new ly absorbed retinol is oxidized to rctinoic acid by class III ADH (ECl.I.l.t; Molotkov er at., 2002). Rctinoic acid is exported through an unknown pathway into poriaf blood and taken up by the liver. Carotenoids: Digestion by the various proteases and peptidases releases carotenoids, if they are attached to proteins. Since carotenoids in plants are embedded in the thylakoid matrix within cells with fairly digestion-resistant walls, cooking or extensive mechanical grinding (chewing) is usually necessary (Rock ei at., 1998). The highest reported beta-carotene bioavailability from carrots, in a finely homogenized preparation, is still less than 3%. however I Edwards et at.. 2002). Carotenoids have to be incorporated into mixed micelles before they can be absorbed (Veum and Russell, 2002). The exact mechanism of carotenoid uptake into enterocytes is uncertain. It does not appear to be very selective.

Carotenoids are incorporated by unknown means into chylomicrons and exported into lymph. Carotenoids take about eight hours after a challenge meal to appear in blood.

Transport and cellular uptake

Blood circulation: The concentration of retinol (about one-tenth as retinyl ester) in plasma is homeostatically maintained around 2 jimol I in men, and closer to 1.7 pmol/l in women (Food and Nutrition Board. Institute of Medicine. 2002: Appendix (J; Olmedilla etat., 1994). On its first pass from portal blood through the liver, retinol is taken Lip into hepatocytes through an unknown mechanism. It can then be resccreted with retinol-binding protein 4 (RBP4). RBPsare lipocalins. w hich means that the protein engulfs a retino! molecule and shields it from the hydrophilic environment in circulation or inside cells. After its release from the liver RUN combines in blood with transthyretin (Episkopou etal.. 1993). A surface receptor on many peripheral cells binds RBP4 and mediates the uptake of the bound retinol. Some epithelial cells, including those in epididymis, thyroid parathyroid and endometrium, express the facultive RBP receptor mcgalin. This member of the LDL-receptor family deliv ers the RBP-bound retinol to the cell by endocytosis. In vitA deficiency, the production and release of RÜP4 by the liver increases.

About Í). 19 jjimol/f beta-carotene. 0.22 p.mol/1 beta-cryptoxanthin. and 0.04 p. mo I '1 alpha-carotene circulate with plasma (Rui/ Rejon el al., 2002). Chylomicrons carry much of the recently ingested carotenoids, They rapidly lose triglycerides, but not carotenoids, and the depleted chylomicron remnants are taken up into hepatocytes and extiahepalic cells \ ia diverse lipoprotein receptors. Low-density lipoproteins (LDL) and high-density lipoproteins (HDL) also carry some carotenoids and bring them into cells when they are taken up through their typical receptor-mediated endocytotic pathways. Blood brain barrier: The pathways for transfer of carotenoids from blood into brain are not well understood.

Materno-fetal transfer: Mega I m. which is expressed in syntrophoblasts. binds and internalizes RBP (Chrislenscn and Birn. 201)1). How much this pathway contributes to \ it A transfer across the placenta is noi known. Another putative RBP receptor has been identified (Johansson et al.. 1999). To some extent retinol can also be esterilied and stored in villous mesenchymal fibroblasts of the placenta (Sapin et al.. 2000),

Metabolism

Retinol and its provitamin A precursors are convened into active metabolites in tissue-specific patterns. Oxidation of rctinoic acid is the only known inactivating cata-bolic pathway. Among the metabolites with functional importance are retinol itself, all-trans-retinal and I l-eis-retinal (vision), a 11-trans-rctinoic acid. 9-cis-retinoic acid 13-cis-retinoic acid and 14-hydroxy-retroretinol. li may be safely assumed that not all enzymes with significant vitA metabolic activity are known, yet. The picture is additionally complicated by the extensive overlapping activity spectra of the various enzymes involved,

All-trans retinoic acid synthesis: Conversion of retinol \ ia retinal to rctinoic acid requires two successive oxidation reactions. Among the widely expressed dehydrogenases suitable for the first oxidation are alcohol dehydrogenases 1 (ADM 1. ECl ,1.1.1, contains zinc), 4 (ADH4), and 7 IADH7, in the cytoplasma of epithelial cells of the stomach). Aldehyde dehydrogenase 1 (ALDH1) and retinal dehydrogenase 2 (RALDH2. ECl .2.1.36. contains FAD) usually complete rctinoic acid synthesis (Duester. 20(H)). All-trans-retinoic acid is quantitatively the predominant isomer. 9-cis-retinoic add Liver, kidneys, small intestine and other tissues produce the 9-cis isomer of rctinoic acid that is functionally and metabolically distinct from the all-trans isomer (Zhuang ei al.. 2002). The enzyme responsible for conversion of all-trans-retinol to 9-cis-retinol is not known. The isoenzymes I and 3 of eis-retinol androgen

Al I-trans-retinol

ADH1 J or 7

NAD * nadh

cis-retincl; androgen dehyarogenasü or RDHS

,NAD

r HO

,NAD

r HO

All-trans-retinal

ADH1 J or 7

NAD * nadh cis-retincl; androgen dehyarogenasü or RDHS

All-trans-retinal

13-cis-retlnoic acid

Cytochrome [>1MRAI Itwmo)

O; »foducod t ttavoprnTam

V H,0 -> oxidized llavupralem

O OH

Cytochrome P4SGRAI (hems!

O OH O; +reaoceil f flavoprrHoin

13-cis-retlnoic acid

Cytochrome [>1MRAI Itwmo)

O; »foducod t ttavoprnTam

V H,0 -> oxidized llavupralem

O 4-0*0-alt-trans-1 eli nmc acid

O OH

Cytochrome P4SGRAI (hems!

O OH O; +reaoceil f flavoprrHoin

^ HjO * oxidized IliivoprtiKiin

^ HjO * oxidized IliivoprtiKiin

Ö 4-oxo-9-cis-retincHcacid

Ö 4-oxo-9-cis-retincHcacid

0 OH

Figur« 9.7 Retinol is ihr precursor of several rctinoic acid isomers dehydrogenase (no EC number assigned) and retinol dehydrogenase (RDH5) oxidize 9-eis-retinol to 9-cis-retinal, Enzymes that accept this isomer as a substrate for further oxidation to 9-cis-retinoio acid include RALDHt. RALDH2, and ALDH12. A retinol dehydrogenase (cRDM, ECU. 1.105) specifically oxidizes 9-cis-retinol to9-eis-retinal, particularly early in fetal development (Gambleelai., 1999). Beta-carotene may also he converted directly into rctinoic acid.

Retinoic add breakdown: Cytochrome p450RAI-l (CYP26A1) in liver and many other tissues and p450RAl-2 (CYP26BI) in brain o.xidi/es retinoic acid to 4-hydroxy rctinoic acid, 4-oxo-retinoic acid, and 18-hydroxy retinoic acid. and thereby contributes to rctinoic acid clearance (White el al., 2000). Microsomal NADPH-ferrihe-moprotein reductase (NADPH-cytochromc P450 oxidnreductase, EC 1,6.2.4, contains FMN and FAD) is the fiavoprotem that provides the electrons for this reaction. Both p450RAI-l and p450RAI-2 prefer all-trans-retinoic acid, but also catabolize 9-cis-netinoic acid and 13-cis-retinoie acid, though wHh lower activity. The ethanol-induciblc cytochrome CYP2E1 also inactivates retinoic acid (Liu el <//.. 2001).

3,4-Didehydroretwol: This metabolite (vitamin A2) is produced in keratinocytes and other skin cells through a poorly understood mechanism (Andersson et «/., 1994). The conversion appears to be irreversible and controlled hy all-trans-relinoic acid (Randolph and Simon, 199fi). Kurt her oxidation hy one or several of the previously described retinal oxidizing enzymes can then generate the 3.4-didehydroretinoic acid, which is a potent metabolite (Sani eta!., 1997), It may be lack of this derivative that causes the typical scaly skin lesions and the production of abnormally large keratins during vitA deficiency (Olson. 1994).

Hydroxyicited retinoids: Most body tissues can add a hydroxyl group to retinol and generate metabolites with distinct biological and metabolic properties. Conversion of retinol to l4-hydroxy-4.l4-retro-retmol 114-11RR), 13.14-dthydroxyretmol. anhydro-retinol, and 4-hydro-5-hydroxy-anhydroretinol. but not to rctinoic acid analogs, has been demonstrated in the liver (Mao et id.. 2(H)!)). The enzymes and other specific proteins involved in most of these conversions remain to be identified however. In l4-hvdroxy-4.14-retro-retinol (14-IIRR) and anhydroretinol the double bonds of the retinoid side-chain are shitted towards the ring system. A phosphoadenosine 5'-phos-pho-sulfate (PAPSJ-requirmg retinol dehydratase (no F.C number assigned) generates anhydroretinol from retinol in insects and fish, but no corresponding human enzyme has vet been identified (Pakhomova et id.. 2001).

Figure 9.8 Thf potent retinol metabolite 3,4-didehydroreunoic acid is produced in stun

Figure 9.8 Thf potent retinol metabolite 3,4-didehydroreunoic acid is produced in stun

14 - Hydroxy-4,14 -retroretinol

14 - Hydroxy-4,14 -retroretinol

Anhydroretinol

Anhydroretinol

4 - H vdro- 5- hydroxy-anh yd roreti not

4 - H vdro- 5- hydroxy-anh yd roreti not

Figur» 9.9 Hydroxylated ntmol metabolite*

Storage

Most cSOVb) of the body's vitA reserves (around 450 mg) of healthy vitA-rcplete adults are stored in liver (500 (xg g wet tissue; Leo and Lieber, 1999). This amount can cover requirements for several months. The vn A in liver resides mainly as retinyl pal nutate in lipid globules of hepatocytes (10-20%) and of stellate I Ito) ceils (80-90%). Two enzymes esterify free retinol, retinol O-fatty-aeyltransferase (acvl CoA:retinol acyltransferase. A RAT. EC2.3.1.76) and phosphat i dy Ichol i ne-retinol O-ucy ¡transferase (lecithin: retinol acyltransfcrase. LRAT. EC2.3.1.135}. The stored esters are released through the action ofall-trans-retinyl-palmitate hydrolase (EC'3.1,1.64) or 11 -cis-retmy!-paImitate hydrolase (LC3.1.1.63). High alcohol intakes can mobilize vitA and deplete stores (Leo and Lieber. 1999).

Excretion

Retinoic acid and other metabolites can be conjugated to glucuronide and excreted with bile, I he relatively high efficiency of intestinal absorption for most retinoids minimizes losses, however, and maintains extensiv e euterohepatic cycling.

Several milligrams of retinol are filtered in the kidney, despite the considerable size of the RBP4-transthyretin complex to which retinol is attached. Megalin. a particularly large member of the LDL-rcceptor family, specifically binds RBP4 and mediates its uptake by endocytosis. Recent evidence suggests that RBP4 and its retinol load can proceed through the epithelial cell and return intact into circulation (Marino el ul„ 2001).

Regulation

The availability of retinoic acid in particular tissues is largely controlled by induction ofproducing (ALDHI and RALDI12) and catabolic (cytochrome P450RAI) activities (White et a!.. 2000).

Function

Vision. The vitamin A metabolite 11-cis-retinal is a critical component of the light-detecting complex in the photoreceptor cells of the eye. Interaction w ith a single photon triggers the conversion of the 11-cisto the all-trans isoform. which leads to the release of retinal from the associated pigment protein (opsin) and the start of a signaling cascade. Rapid reduction of the frceall-trans-retinal by retinol dehydrogenase (all-trans-retinol dehydrogenase, EC 1.1.1.105, NAD-dependent) prevents the reversion into the vision-active form (Saari el ah, 1998). Four distinct 11-cis-retinal-contaming rhodopsins (vision pigments) with specific properties enable humans to detect light at particular wavelengths. Rhodopsin in combination with 11-cis-retinal absorbs light with a maximum at 495 um in retinal rods. This pigment gives dual-mode vision (black-and-white), I hrce pigments m the retinal cones, each consisting of a specific cone pigment and l-cis retinal, prov ide color vision. Blue cone pigment absorbs best at 440 nm and gives blue vision. Green cone pigment detects green due to its absorption maximum at 535nm, and red cone pigment detects red and yellow with a maximum at 560 nni.

The retinal pigment epithelium forms a layer between the photoreceptors and the capillary blood supply. The active metabolite. 11-cis-retinal. is produced from retinol by

L 1 Alt-trans-rethiol —-----I Jl Alltrans-retlno!

Reboot

AIMrara-rMnol tJehydrogeniüve

NADH

Pigment epithelium cell Figure 4.1fl Vitamin A metabolism in the retirta

L. JL Alt-lrans-ralinal

11-cis-retirial + opsm = rhottopsm

Photoreceptor cell

Pigment epithelium cell Figure 4.1fl Vitamin A metabolism in the retirta

11-cis-retirial + opsm = rhottopsm

Photoreceptor cell the successive action ofretinol isomerase (EC5.2.1.7)and 11-cis-retinol dehydrogenase (RDH5, no EC number assigned can use NAD as well as NADP). It has been suggested thai cellular retinaldchyde binding protein (CRAL.BP) acts as an acceptor For the 11-cis-retinal intermediate(Saari etal., 2001), Inhibition of RDH5 might contribute to the transient blindness sometimes seen with excessive licorice consumption (Dobbins and Saul. 2000). All-trans-retinaI can also be activated by retinal isomerase(EC5,2.1.3). The pigment epithelial cells also store limited amounts ofvitA as retinylesters. For this purpose phosphatidylcholine-retinol O-acy[transferase (EC2.3.1.135) moves a fatty acid from phospholipid to the R BP 1-bound retinol. The stored esters are released through the actions of all-trans-net inyl-palmitate hydrolase (EC3.1,1 .(i4). I l-cis-retinyl-palmitate hydrolase (EC3.1.1.63), or all-trans-retinylester isomerohydrolase (no EC number assigned). RBP3 (interphotoreceptor retinoid-binding protein. IRBP) is a specific lipocalin in the interstitial space between pigment epithelium and photoreceptors. Its importance may extend more to the surv iv al of photoreceptor cells than to their supply of active 11-cis-retinal (Palczewski el at.. 1999). Nuclear actions: VitA is of vital importance for normal cndodermal differentiation, morphogenesis, regulation of embryonic and childhood development as well as for sustaining balanced cell proliferation, differentiation, and apoptosis in adulthood. Many of the underlying events involve the binding ofvitA-containing receptors to specific binding elements in nuclear DNA and control of the expression of associated genes. Two groups of retinoid receptors have been identified. The first includes the rctmoic acid receptors (RAR) alpha, beta, and gamma. Their ligands are all-trans-ret inoic acid 9-cis-retinoic acid

Figure 9.11 4'QnorciinoJ

4-oxoretinoic acid, 4-oxoretinol. and a few other candidate retinoids. The second group is comprised of the retinoic X receptors alpha, beta, and gamma with 9-cis-retinoic acid as the main activating ligand. The RXR group is particularly interesting because association with them enables the actions of numerous other nuclear receptors. The list of RXR-dependent nuclear binding proteins includes RAR. thyroid receptors (TR). vitamin D receptor (VDR), peroxisome proliferation activating receptors t PPAR), pregnane X receptor (steroid and xcnobiotic receptor. SXR PXR), liver X receptors (LXR). farnesoid X-activated receptor (FXR >, and ben/oatc X receptor (BX R). The diversity of functions becomes evident just from the designations of these receptors. A compilation of published research data indicates more than a hundred genes that are known or likely targets of retinoic acid-mediated action alone I Balmer and BlomhofF. 20(121. Cell cycle and apoptosis: In contrast to the generally growth-promoting properties of the major forms of vitA. anhydroretinol triggers (nonclassical) programmed cell death (Korichncva and Hammer ling. 1999). possibly by inducing oxygen free radical production (Chen el at., 1999). 4-Oxoretinol is able to induce growth arrest and promote differentiation of promyelocytes (Faria eft//., I99.S), Apocarotenoie acids, the metabolites ofexcentric beta-carotene cleavage products, inhibit tumor cell growth through mechanisms that arc distinct from all-tmns-retinoic acid (Tibaduiza i't at., 2002>. Cell signaling: Retinol and some metabolites interact directly w ith phosphokinasc C (PKC" I. a central element of the intracellular signaling cascade (Imam et a!.. 2(H) I). They may do this through binding to specific sites and directing the functionaliy important oxidation of particular cysteines.

References

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Barua AB. Olson JA. /i-carotene is converted primarily to retinoids in rats in viva J Nutr 2000; 130:1996-2001

Chen Y. Buck J, Derguini F. Anhydroretinol induces oxidative stress and cell death.

Cancer Res 1999;59:3985-90 Christensen EI, Bim H. Megabit and cubilin: synergistic endocytic receptors in renal proximal tubule. Am .1 Physiol Renal Fluid Electrolyte Physiol 2001 ;280:F562-573

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