Retinoids Alcohol

Retinoids are alcohols and accordingly soluble in ethanol, isopropanol, and polyethylenglycol. Major sources of natural retinoids are animal fats, fish liver oil (retinylesters) and yellow and green vegetables (carotenoids). Ingested retinylesters (RE) are hydrolyzed to retinol by enteral hydrolases in the intestine. ROL and carotenoids are absorbed by intestinal mucosa cells. 

Increased risk factors for suffering retinoid side effects are adipositas, alcohol abuse, diabetes, nicotine abuse, familiar lipid metabolism alterations and other concommittant therapies (see below). 

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]. 

Adapalene (Differin) is a third-generation retinoid with comedolytic, kera-tolytic, and antiinflammatory activity, ft is available as 0.1% gel, cream, alcoholic solution, and pledgets. A 0.3% gel formulation is also available. 

Further sulfoxide elimination led to the formation of dienoate esters, including a novel retinoid analogue (Eq. 93) [271]. More recent chemistry involved 1,2-Stevens rearrangement to gain access to aminoacid analogues (Eq. 94) [272]. The second strategic use involves the addition of alcohols to the... 

Although the term vitamin A has been used to denote specific chemical compounds, such as retinol or its esters, this term now is used more as a generic descriptor for compounds that exhibit the biological properties of retinol. Retinoid refers to the chemical entity retinol or other closely related naturally occurring derivatives. Retinoids also include structurally related synthetic analogues, which need not have retinol-like (vitamin A) activity. The structural formulas for the vitamin A family of retinoids are shown in Figure 66.3. Retinol (vitamin Aj), a primary alcohol, is present in esterihed form in the tissues of animals and saltwater fish, mainly in the liver. A closely related compound, 3-dehydroretinol (vitamin A2), is obtained from the tissues of freshwater fish and usually occurs mixed with retinol. 

Kedishvili NY, Stone CL, Popov KM, Chernoff EAG. Role of alcohol dehydrogenases in steroid and retinoid metabolism. In Weiner H, Lindahl R, Crabb DW, Flynn TG, eds. Enzymology and Molecular Biology of Carbonyl Metabolism 6. New York Plenum Press, 1996 321-329. 

Preparing a dilute solution of the retinoid extract in either water or an alcohol-based solvent. 

Note carefully that the short wave peak in the curve for the dilute retinoids (alias rhodopsin), and labeled A, does not correspond in wavelength to the peak for any of the in-vitro materials. This is to be expected since the in-vitro experiments are usually performed with an alcohol solvent. Shifts in wavelength of 15-20 nm as a function of solvent are frequently encountered in in-vitro experiments146. 

When the hydrogen ion is considered to be attached to the rightmost end of the Rhodonine ion, Rhodonine will appear to be an alcohol and respond to simple chemical tests almost identically to Retinol. When the hydrogen ion is considered to be attached to C5, Rhodonine will appear to be an aldehyde and respond to simple chemical tests almost identically to retinaldehyde. The chemical ambiguity in the properties of the Rhodonines due to this resonance condition is the principle practical reason for the confusion in the literature concerning the chemical properties of the chromophores of vision. The principal conceptual reason is the prior failure of the community to recognize the existence of the resonant form of the retinoids, the Rhodonines. 

Alcohol gel HPLC SPE, C OSD-2, MeOH-THF-0.025M 300 nm Retinoid stability... 

The crucial intermediacy of cyclopropylcarbinyl species in the biological synthesis of hundreds (thousands) of steroids, carotenoids, retinoids and derivatives is exemplified by the C30 presqualene pyrophosphate (77) and the C40 prephytoene pyrophosphate (89). In the biosynthetic construction of the key C(l)-C(l) carbon-carbon in head-to-head joining of Cl 5 or C20 alkyl alcohol pyrophosphate esters, the cyclopropylcarbinyl strategy via a formal insertion of C(l) of one monomer into the C(2)-C(3) double bond of the second monomer appears to be the central mechanistic solution in the biochemical inventory. The cyclopropylcarbinyl pyrophosphate forms as obligate intermediate whether the final... 

In contrast to retinoids, carotenoids were considered non-toxic, even when taken chronically in large amounts, until recently, when it was found that ethanol interacts with carotenoids, interfering with their conversion to retinol. In baboons, the consumption of ethanol together with beta-carotene resulted in more striking hepatic injury than consumption of either compound alone (98). This interaction occurred at a total dose of 7.2-10.8 mg of beta-carotene per Joule of diet. This dose is common in people who take supplements and is the same order of magnitude used in the Beta-Carotene and Retinol Efficacy Trial (CARET) (30 mg/day) (99) and in another study (20 mg/day for 12 weeks) (100). The amount of alcohol given to the baboons was equivalent to that taken by an average alcohohc. The well-known toxicity... 

As detrimental effects result from deficiency as well as an excess of retinoids and carotenoids, and since both have similar adverse effects in terms of fibrosis, carcinogenesis, and possibly embryotoxicity, therapeutic measures must pay attention to the narrow therapeutic window, especially in drinkers, in whom alcohol narrows the therapeutic window even further by promoting the depletion of retinoids and by potentiating their toxicity (91). 

In the case of CRBP and CRBPII, a number of retinoids have been tested (MacDonald and Ong, 1987 Cheng et al., 1991). No binding to CRBP or CRBPII occurred with 9-c - or 11-cis-retinol. However, binding was detected with 13-cis-retinol and 3-dehydroretinol. One unusual finding was that CRBPII but not CRBP had a detectable affinity for all-tram-retinaldehyde. Later studies (Li et al., 1991) showed that CRBP could bind retinol or retinal but that it had a 100-fold higher affinity for the alcohol. 

Fig. 1. The structures of key retinoids and their precursors. Fish convert retinyl esters (e.g. retinyl palmitate (RP)) and carotenoids (e.g. /3-carotene) to retinol in the gut lumen prior to intestinal absorption. Retinyl esters (e.g. RP) stored in the liver are synthesized from retinol by lecithin retinol acyltransferase (LRAT) and acyl CoAiretinol acyltransferase (ARAT). The retinyl esters are mobilized through their conversion to retinol by retinyl ester hydrolase (REH), which is then transported in the circulation to various sites in the body. Retinol is further metabolized within specific tissues to retinal by alcohol dehydrogenases (ADH) or short-chain dehydrogenase/reductase. Retinal is converted to the two major biologically active forms of retinoic acid (RA) (all-trans and 9-cis RA). Retinaldehyde dehydrogenase 2 (Raldh2) synthesizes all-trans RA from all-trans precursors and 9-cis RA form 9-cis precursors.

Adapalene, a third-generation retinoid, is a retinoid-mimetic com-ponnd (a naphthoic acid derivative), available as 0.1% gel, cream, alcoholic solntion, and pledgets. It has selective affinity for retinoic acid receptor (RAR) subtypes RAR- 8 and RAR-y fonnd in the epidermis," " " and has comedolytic, keratolytic, and anti-inflammatory activity. " " " Vehicle-controlled and comparative stndies have demonstrated the utility of adapalene in treatment of acne." " " Adapalene is indicated for mild to moderate acne vnlgaris. Adapalene 0.1% gel may be used as an alternative to tretinoin 0.025% gel to achieve better tolerability in some patients." " Adapalene coadministered with a topical or oral antibiotic represents arational therapy for moderate forms of acne."... 

Tretonin cream, a topical retinoid, contains tretinoin 0.025% by weight in a hydrophilic cream vehicle of stearic acid, polyolprepolymer-2, isopropyl myristate, polyoxyl 40 stearate, propylene glycol, stearyl alcohol, xanthan gum, sorbic acid, butylated hydroxytoluene, and purified water. The tretinoin cream 0.02% contains the active ingredient tretinoin in a cream base. It is available at a concentration... 

This class of vitamins comprises a group of molecules which are also known as retinoids and also includes certain carotenes which display vitamin A-like activity (particularly a-, and y-carotene from plants). Many derivatives of these compounds are found naturally and include the alcohol, the acetate and the palmitate. The best chromatographic mode for the resolution of the vitamin A class is often determined by the conditions used for the extraction. For example, saponification to remove lipids is often followed by extraction into solvents, such as hexane, which are compatible with aqueous reversed phase HPLC using either a Cg or C,g siUca-based stationary phase (Fig. 11.8.1). An alternative system has been reported using a Cjg support and a mobile phase of 0.5% acetic acid in acetonitrile (Annesley et al., 1984). 

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