Retinol to retinoic acid

Deltour L, Foglio MH, Deuster G. Metabolic deficiencies in alcohol dehydrogenase Adhl, Adh3, and Adh4 null mutant mice Overlapping roles of Adhl and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid. J Biol Chem 1999 274 16796-16801. 

Cytosolic alcohol dehydrogenases only act on free retinol, not retinol bound to CRBP, so they are unlikely to he involved in formation of retinaldehyde and retinoic acid. Furthermore, inhihition of cytosolic alcohol dehydrogenases does not inhibit the oxidation of retinol to retinoic acid (Boerman and Napoli, 1996). CRBP-bound retinol is a substrate for atleast three microsomal NADP+-dependent dehydrogenases hut, given the intracellular NADP+ NADPH ratio (0.01, compared with an NAD+ NADH ratio of the order of 10 ), it is likely that these microsomal enzymes wiU act mainly to reduce retinaldehyde to retinol and not to oxidize retinol. 

In adults, excessive alcohol consumption reduces liver reserves of vitamin A, both as a result of alcoholic liver damage and also by induction of cytochrome P450 enzymes that catalyze the oxidation of retinol to retinoic acid (as also occurs with chronic use of barbiturates). However, chronic consumption of alcohol can also potentiate the toxicity of retinol (Section 2.5.1). 

CRBP is thought to assure that retinol is metabolized by specific enzymes, while preventing metabolism by other enzymes. For example, by binding retinol, CRBP prevents excessive rates of conversion of retinol to retinoic acid (Napoli, 1996). 

The specific role of vitamin A in tissue differentiation has been an active area of research. The current thinking, developed in 1979, involves initial dehvery of retinol by holo-B >V (retinol-binding protein) to the cell cytosol (66). Retinol is then ultimately oxidized to retinoic acid and binds to a specific cellular retinoid-binding protein and is transported to the nucleus. Retinoic acid is then transferred to a nuclear retinoic acid receptor (RAR), which enhances the expression of a specific region of the genome. Transcription occurs and new proteins appear during the retinoic acid-induced differentiation of cells (56). 

Kang et al. [23] compared the clinical, histologic, and molecular responses of normal human skin to topical retinol with that of retinoic acid. Application of retinol and retinoic acid produced epidermal thickening. However, retinol produced less erythema compared with retinoic acid. The authors suggest that these data are compatible with the idea that retinol may he a pro-hormone of retinoic acid. 

Vitamin A (retinol) and retinoic acid are carotenoid oxidation compounds that are very important for human health. The main functions of retinoids relate to vision and cellular differentiation. With the exception of retinoids, it was only about 10 years ago that other carotenoid oxidation products were first thought to possibly exert biological effects in humans and were implicated in the prevention - or promotion of degenerative diseases. A review on this subject was recently published. ... 

The central cleavage of P-carotene 1 is most likely the major pathway by which mammals produce the required retinoids il), in particular, retinal 2, which is essential for vision and is subsequently oxidized to retinoic acid 3 and reduced to retinol 4. An alternative excentric cleavage of 1 has been reported involving scission of the double bond at C7-C8 producing P-8 -apocarotenal 5 (2a,2b) which is subsequently oxidized to 2 (Fig. 1) (2c). The significance of carotene metabolites such as 2, 3 and 4 to embryonic development and other vital processes such as skin and membrane protection is a major concern of medicinal chemistry. 

Retinyl esters and the P-carotene are incorporated into chylomicrons and taken up mainly by hepatocytes. In the liver retinol may be stored in stellate cells as retinyl esters, oxidized to retinoic acid or liberated into cells bound to retinol-binding proteins (RBP). All E retinoic acid and its 9Z isomer have an affinity for nuclear receptors. They activate the transcription and bind as dimers to specific nucleotide sequences, present in promoters of target genes. 

Retinol can be oxidized to retinal (6.2) and further to retinoic acid (6.3). Cis-trans isomerization can also occur, e.g. the conversion of all trans-retinal to 11-cis-retinal (6.4), which is important for vision. 

Retinol is oxidized to retinoic acid, which binds to nuclear receptors. 

Retinol is oxidized to retinoic acid. Movement from cytosol to nucleus is guided by cellular retinol-binding proteins and cellular retinoic acidbinding proteins. 

Free retinol is released from the liver as a 1 1 complex of retinol with the 21-kDa retinol-binding protein.k l This protein is normally almost saturated with retinol and is bound to another serum protein, the 127-residue transthyretin (prealburnin).m/n Some of the retinol is oxidized to retinoic acid. 

Much recent interest has been aroused by the fact that retinoid compounds, including both retinol and retinoic acid, reduce the incidence of experimentally induced cancer. In addition, 13-czs-retinoic acid taken orally is remarkably effective in treatment of severe cystic acne. s However, both vitamin A and retinoic acid in large doses are teratogenic, i.e., they cause fetal abnormalities. The use of 13-cis-retinoic acid during early phases of pregnancy led to a high incidence of major malformations in infants born.1 11 1... 

Dietary vitamin A is stored in the liver and secreted into the bloodstream when needed. The circulating retinol is taken up by target cells and oxidized in part to retinoic acid, which induces the synthesis of proteins through the direct control of gene expression. This type of action—gene activation—establishes vitamin A (in the form of its metabolite, retinoic acid) as a hormone, similar to the steroid hormones and the thyroid hormone. 

Structurally, vitamin A and many synthetic retinoids consist of a (3-ionone ring, a polyunsaturated polyene chain, and a polar end group. The polar end group can exist in several oxidation states, as retinol, retinal, or retinoic acid. Retinol and retinyl esters are the most abundant vitamin A forms found in the body (Blaner and Olson, 1994). Retinol can be esterified with long-chain fatty acids (mainly palmitate, oleate, and stearate) to form retinyl esters, which are the body s storage form of vitamin A. Retinol also can undergo oxidation to retinal, which can be oxidized further to retinoic acid. The active... 

Retinoic acid is a metabolic product of vitamin A that supports the growth and differentiation of epithelial tissues. Retinoic acid is formed in the cytosol by the reversible oxidation of retinol to retinal, and the irreversible oxidation of retinal to retinoic acid. There is controversy as to whether retinal is oxidized by retinal dehydrogenase, which is linked to NAD+, or by retinal oxidase. 

Retinoic acid regulates its own synthesis from retinol in a variety of tissues by induction of LRAT this increases the rate of esterification of retinol, thereby decreasing the amount available for oxidation to retinoic acid (Kurlandsky et al., 1996). Retinoic acid also induces the cytochrome P450 that catalyzes oxidation to 4-oxo-retinoic acid, and regulates both its own synthesis and catabolism. 

Vitamin A-deficient experimental animals fail to grow adults are blind and sterile, with testicular degeneration in males and keratinization of the uterine epithelium in females. Although deficient female animals wUl conceive, and the fetuses will implant, formation of the placenta is impaired and the fetuses are resorbed. Epithelia in general are hyperplastic and keratinized, and there is impaired cellular immunity with increased susceptibility to infection. Both retinol and retinoic acid are required for gestation in the rat in deficient animals, retinoic acid alone will not prevent fetal resorption after about day 10 of gestation (WeUik and DeLuca, 1995 WeUik et al., 1997). 

Dickson IR, Walls J, and Webb S (1989) Vitamin A and bone formation. Different responses to retinol and retinoic acid of chick bone cells in organ culture. Biochimica et BiophysicaActa 1013,254-8. 

Wellik DM and DeLuca HE (1995) Retinol in addition to retinoic acid is required for successful gestation in vitamin A-deflcient rats. Biology and Reproduction 53,1392-7. 

A small proportion of dietary retinol is oxidized to retinoic acid, which is absorbed into the portal circulation and bound to serum albumin. Some retinyl esters tue also ti Einsferred into the ported circulation. Patients with abeta-lipoproteinemia, who ar e unable to synthesize chylomicrons, can nevertheless maintain adequate vitamin A status if they are provided with relatively high intakes of retinol. 

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