Retinol oxidation

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

ChenH, Howald WN, and Juchau MR (2000) Biosynthesis of all-fraws-retinoic acid from all-fraws-retinol catalysis ofall-trfl s-retinol oxidation by human P-450 cytochromes. Drug Metabolism and Disposal 28, 315-22. 

Mertz JR, Shang E, Pianedosi R, Wei S, Wolgemuth DJ, Blaner WS (1997) Identification and characterization of a stereospecific human enzyme that catalyzes 9-cw-retinol oxidation a possible role in 9-cw-retinoic acid formation. 7 Bio/ Chem 212 11 744-11 749... 

The recent identification of 9-cw-retinol dehydrogenase in the mouse embryo reveals a pathway for 9-cw-RAs synthesis in this species [60]. This membrane-bound enzyme is able to oxidize 9-c/5-retinol into 9-c/5-retinaldehyde which can be subsequently oxidized to 9-cis-RA. The expression of this enzyme is temporally and spatially controlled during embryogenesis in parts of the nervous system, sensory organs, somites and myotomes, and several tissues of endoder-mal origin. Mertz et al. have also identified a stereospecific human enzyme that catalyzes 9-cis-retinol oxidation and is likewise a member of the short chain alcohol dehydrogenase protein family [61]. The mRNA for the protein is most abundant in human mammary tissues. 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

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). 

The retinol that is delivered to the retinas of the eyes in this manner is accumulated by rod and cone cells. In the rods (which are the better characterized of the two cell types), retinol is oxidized by a specific retinol dehydrogenase to become 2iW-trans retinal and then converted to 11-eis retinal by reti-... 

FIGURE 18.36 The incorporation of retinal into the light-sensitive protein rhodopsin involves several steps. All- ram-retinol is oxidized by retinol dehydrogenase and then iso-merized to ll-cis-retinal, which forms a Schiff base linkage with opsin to form light-sensitive rhodopsin. 

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. ... 

Moreover in the retina, iron is a cofactor of a number of other enzymes, including nitric oxide synthase, (i-carotene monooxygenase, and RPE65-isomerohydrolase converting all-tranx-retinol to 11 -m -retinol in the visual cycle. 

Retinoic acid Retinol (vitamin A) oxidation Zn finger ( ) ... 

This photoaffinity labelling analogue of all-fraws-retinal, 95b, has been tritium labelled80 by reduction of unlabelled aldehyde 95a with [3H]-NaBH4 and subsequent oxidation of the obtained tritium-labelled retinol with activated manganese dioxide. The product 95b (specific activity 38.3 mCimmol-1) has been isolated by preparative TLC (equation 36). 

This reaction was also used in a synthesis of 13-cis-retinoic acid.2 Thus reduction of 3 under the same conditions gives the triethylsilyl ether (4) of 13-cis-retinol, with retention of the geometry of the terminal double bond. This product can be converted to 13-cis-retinoic acid by deprotection and oxidation (60% yield). 

The ALDs are a subset of the superfamily of medium-chain dehydrogenases/reductases (MDR). They are widely distributed, cytosolic, zinc-containing enzymes that utilize the pyridine nucleotide [NAD(P)+] as the catalytic cofactor to reversibly catalyze the oxidation of alcohols to aldehydes in a variety of substrates. Both endobiotic and xenobiotic alcohols can serve as substrates. Examples include (72) ethanol, retinol, other aliphatic alcohols, lipid peroxidation products, and hydroxysteroids (73). 

The a-, (3- and y-carotenes, which are found in most plants, are vitamin A provitamins and are converted to vitamin A alcohol (all- ran,v-retinol), which is usually called vitamin Aj (Figure 12.8) by oxidative mid-point cleavage. Retinol and its fatty acid esters are the main forms in which vitamin A is stored in animals and humans, and its oxidation product, 1 1-c/s-retinal (vitamin A, aldehyde), is required for the visual process. 

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. 

The solid matrix of SLN protects the drug from hydrolysis and oxidation. Chemical stability of tocopherol and retinol improves considerably [17,39], with tocopherol improving by 57% compared with an aqueous dispersion. The degree of retinol stabilization depends on the nature of lipid and surfactant [39]. For each drug, the optimal preparation has to be defined individually. 

For vision to continue, c/s-retinal must be regenerated. The /rans-retinal is reduced to /rans-retinol (i.e. the aldehyde is converted to alcohol) and is isomerised to c/s-retinal this is oxidised to c/s-retinol (see Figure 15.9(b)). Two different cells are involved the oxidation of retinal to retinol occurs in the photoreceptor cell. The retinol is then released and is taken up by the adjacent epithelial cell where it is isomerised to c/s-retinol and then reduced to... 

Figure 15.11 The biochemical reactions that result in the conversion of trans-retinal to ds-retinal, to continue the detection of light To continue the process, trans-retinal must be converted back to c/s-retinal. This is achieved in three reactions a dehydrogenase converts trans-retinal to trans-retinol an isomerase converts the trans-retinol to c/s-retinol and another dehydrogenase converts c/s-retinol to c/s-retinal. To ensure the process proceeds in a clockwise direction (i.e. the process does not reverse) the two dehydrogenases are separated. The trans-retinal dehydrogenase is present in the photoreceptor cell where it catalyses the conversion of trans-retinal to trans-retinol which is released into the interstitial space, from where it is taken up by an epithelial cell. Here it is isomerised to c/s-retinol and the same dehydrogenase catalyses its conversion back to c/s-retinal. This is released by the epithelial cell into the interstitial space from where it is taken up by the photoreceptor cell. This c/s-retinal then associates with the protein opsin to produce the light-sensitive rhodopsin to initiate another cycle. The division of labour between the two cells may be necessary to provide different NADH/NAD concentration ratios in the two cells. A high ratio is necessary in the photoreceptor cell to favour reduction of retinal and a low ration in the epithelial cell for the oxidation reaction (Appendix 9.7).

Terpenoid DBPs were investigated by Joll et al. [124] and Qi et al. [125]. The main ozonation product of 2-methylisobomeol was camphor, which was further oxidized to formaldehyde, acetaldehyde, propanal, buntanal, glyoxal, and methyl glyoxal [125]. Chlorination of p-carotene, retinol, p-ionone, and geranyl acetate resulted in the formation of THMs [124]. 

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