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At least 19 recordsLinked to original sources
PubMed1999

Metabolism of retinaldehyde isomers in pregnant rats: 13-cis- and all-trans-retinaldehyde, but not 9-cis-retinaldehyde, yield very similar patterns of retinoid metabolites.

Retinaldehyde (RAL), a key intermediate in retinoid metabolism, acts as a retinoic acid (RA) precursor, but is also reduced to retinol (ROH), which can subsequently be esterified to retinyl esters, the storage form of vitamin A. Limited information is available on the metabolism of geometric isomers of RAL as well as on the transplacental distribution of their metabolites, including RA isomers. Such information would be very helpful for the assessment of the teratogenic potency of RAL isomers, as teratogenesis represents a major side effect of retinoid use in pharmacotherapy. In the present study we examined concentrations of retinoids in plasma, maternal tissues, and embryos of pregnant rats 2 h after a single oral dose (100 mg/kg body weight) of all-trans-, 13-cis-, or 9-cis-RAL on gestational day 13. The main findings of this study were the very similar patterns of retinoid metabolites (consisting of retinoids with mainly the all-trans-configuration) after administration of all-trans- and 13-cis-RAL, and the high concentrations of 9-cis-RA, 9,13-dicis-RA, and 9-cis-retinoyl-beta-D-glucuronide after dosing with 9-cis-RAL. In addition, all-trans-RA as a RAL metabolite reached the embryos to a much greater extent than any of its cis-isomers. The results are discussed in view of in vitro data on enzymes involved in the biotransformation of RAL isomers.

Animals↗
PubMed1987

Binding of 11-cis retinaldehyde to the partially purified cellular retinaldehyde binding protein from bovine retinal pigment epithelium.

11-cis retinaldehyde binding analysis was performed on a bovine retinal pigment epithelium preparation of cellular retinaldehyde binding protein (CRALBP), whose purity degree was estimated as 75%. Equilibrium binding studies were carried out measuring the replacement of tritium-labeled with unlabeled 11-cis retinaldehyde at 25 degrees C. Analysis of the experimental data both by a direct curve-fitting procedure utilizing a non linear least square regression analysis and by a conventional Scatchard plot revealed a single non-interacting binding site with an apparent equilibrium constant of 0.9 X 10(-7) M. A binding stoichiometry of approximately 1 mol of 11-cis retinaldehyde/mol of binding protein can be calculated from the experimental data. Competition studies carried out in the presence of unlabeled 'trans' and 'cis' isomers of vitamin A derivatives confirm the high degree of specificity of the 11-cis retinaldehyde binding.

Animals↗
PubMed1987

Photochemistry and stereoselectivity of cellular retinaldehyde-binding protein from bovine retina.

11-cis-Retinaldehyde bound to cellular retinaldehyde-binding protein (CRALBP) is unaffected in bovine eyecup preparations by illumination that bleaches approximately 70% of the rhodopsin. Illumination of retinal homogenates to which CRALBP X [3H]11-cis-retinaldehyde had been added did not result in a reduction of the specific activity of recovered 11-cis-retinaldehyde, ruling out a bleaching regeneration cycle. The quantum efficiency of photoisomerization for CRALBP X 11-cis-retinaldehyde was determined by comparing the rate of photoisomerization of 11-cis-retinaldehyde bound to purified CRALBP and opsin. The low value obtained (0.07), coupled with a low molar extinction coefficient (15,400 M-1 cm-1), results in a photosensitivity only about 4% that of rhodopsin. CRALBP binds 9-cis- and 11-cis-retinaldehyde, producing complexes with absorption maxima at 405 and 425 nm, respectively. No complexes were detected with 13-cis- and all-trans-retinaldehyde. Following incubation of CRALBP X 11-cis-retinol with an equimolar mixture of 9-, 11-, 13-cis-, and all-trans-retinaldehydes, only 11-cis-retinaldehyde and residual 11-cis-retinol are present on the protein following separation from excess retinoids. A similar result is obtained following incubation of CRALBP X 11-cis-retinol with mixtures of 9- and 11-cis-retinaldehyde ranging in composition from 9:1 to 1:9 (9-cis-:11-cis-,mol/mol). The results indicate that CRALBP X 11-cis-retinol is sufficiently stereoselective in its binding properties to warrant consideration as a component of the mechanism for the generation of 11-cis-retinaldehyde in the dark.

Animals↗
PubMed1999

Metabolism of retinaldehyde and other aldehydes in soluble extracts of human liver and kidney.

Purification and characterization of enzymes metabolizing retinaldehyde, propionaldehyde, and octanaldehyde from four human livers and three kidneys were done to identify enzymes metabolizing retinaldehyde and their relationship to enzymes metabolizing other aldehydes. The tissue fractionation patterns from human liver and kidney were the same, indicating presence of the same enzymes in human liver and kidney. Moreover, in both organs the major NAD(+)-dependent retinaldehyde activity copurified with the propionaldehyde and octanaldehyde activities; in both organs the major NAD(+)-dependent retinaldehyde activity was associated with the E1 isozyme (coded for by aldh1 gene) of human aldehyde dehydrogenase. A small amount of NAD(+)-dependent retinaldehyde activity was associated with the E2 isozyme (product of aldh2 gene) of aldehyde dehydrogenase. Some NAD(+)-independent retinaldehyde activity in both organs was associated with aldehyde oxidase, which could be easily separated from dehydrogenases. Employing cellular retinoid-binding protein (CRBP), purified from human liver, demonstrated that E1 isozyme (but not E2 isozyme) could utilize CRBP-bound retinaldehyde as substrate, a feature thought to be specific to retinaldehyde dehydrogenases. This is the first report of CRBP-bound retinaldehyde functioning as substrate for aldehyde dehydrogenase of broad substrate specificity. Thus, it is concluded that in the human organism, retinaldehyde dehydrogenase (coded for by raldH1 gene) and broad substrate specificity E1 (a member of EC 1. 2.1.3 aldehyde dehydrogenase family) are the same enzyme. These results suggest that the E1 isozyme may be more important to alcoholism than the acetaldehyde-metabolizing enzyme, E2, because competition between acetaldehyde and retinaldehyde could result in abnormalities associated with vitamin A metabolism and alcoholism.

Aldehyde Oxidoreductases↗
PubMed1988

Reduction of retinaldehyde bound to cellular retinol-binding protein (type II) by microsomes from rat small intestine.

Cellular retinol-binding protein, type II (CRBP (II], an abundant protein of the rat small intestine, has recently been shown to be able to bind retinaldehyde in addition to retinol (MacDonald, P.N., and Ong, D. E. (1987) J. Biol. Chem. 262, 10550-10556). Retinaldehyde is produced in the intestine by oxidative cleavage of beta-carotene. The next step in the intestinal metabolism of vitamin A is the reduction of retinaldehyde to retinol which is then esterified for incorporation into chylomicrons. In the present study retinaldehyde bound to CRBP(II) was found to be available for reduction by microsomal preparations from rat small intestinal mucosa. The microsomal activity was about 8 times greater than the activity observed for an equal amount of cytosolic protein. Retinaldehyde reduction utilized either NADH or NADPH as cofactor, with NADH being slightly more effective. The apparent Km for retinaldehyde-CRBP(II) was 0.5 microM, and the Vmax was approximately 300 pmol/min/mg protein, a rate more than sufficient for the needs of the animal. The product retinol remained complexed to CRBP(II). The microsomal enzyme activity reduced free and bound retinaldehyde to approximately the same extent, although the aldehyde function of retinaldehyde bound to CRBP(II) was less accessible to chemical reducing agents than that of free retinaldehyde. Retinol bound to CRBP(II) could not be oxidized by the microsomal activity in the presence of NAD+, while free retinol or retinol bound to bovine serum albumin was oxidized to retinaldehyde. The more favorable reduction versus oxidation of retinoid bound to CRBP(II) consequently favored the reaction known to be required for the ultimate conversion of beta-carotene to retinyl esters for export from the gut.

Animals↗
PubMedDate not supplied

Retinaldehyde, a potent inhibitor of gap junctional intercellular communication.

Retinaldehyde and retinoic acid are derivatives of vitamin A, and retinaldehyde is the precursor for the synthesis of retinoic acid, a well-known inhibitor of gap junctional intercellular communication. In this investigation, we asked the question if retinaldehyde has similar effects on gap junctions. Gap junctional intercellular communication was measured by scrape-loading and preloading dye-transfer methods, and studies were carried out mainly on cultured liver epithelial cells. Retinaldehyde was found to be a more potent inhibitor (dye transfer reduced by 50% at 2.8 microM) than retinoic acid (dye transfer reduced by 50% at 30 microM) and glycyrrhetinic acid (dye transfer reduced by 50% at 65 microM). Both the 11-cis and all-trans forms of retinaldehyde were equally effective. Retinaldehyde inhibited dye transfer of both anionic Lucifer yellow and cationic Neurobiotin. Inhibition by retinaldehyde developed in less than two minutes at 50 microM, but unlike the reported case with retinoic acid, recovery was slower, though full. In addition to liver epithelial cells, retinaldehyde inhibited gap junctional communication in lens epithelial cells, retinal pigment epithelial cells and retinal ganglion cells.

Animals↗
PubMed1996

Topical retinaldehyde increases skin content of retinoic acid and exerts biologic activity in mouse skin.

Retinaldehyde, a natural metabolite of beta-carotene and retinol, has been proposed recently for topical use in humans. Because retinaldehyde does not bind to retinoid nuclear receptors, its biologic activity should result from enzymatic transformation by epidermal keratinocytes into ligands for these receptors, such as all-trans retinoic acid and 9-cis-retinoic acid. In this study, we analyzed by high performance liquid chromatography the type and amounts of tissue retinoids as well as several biologic activities resulting from topical application of either retinaldehyde or all-trans retinoic acid on mouse tail skin. Biologic activities of all-trans retinoic acid and retinaldehyde were qualitatively identical in metaplastic parameters (induction of orthokeratosis, reduction of keratin 65-kDa mRNA, increase in filaggrin and loricrin mRNAs) and hyperplastic parameters (increase in epidermal thickness, increase in bromodeoxyuridine (BrdU)-positive cells, increase in keratin 50-kDa mRNA, and reduction in keratin 70-kDa mRNA). Some quantitative differences, not all in favor of all-trans retinoic acid, were found in several indices. Cellular retinoic acid-binding protein II and cellular retinol-binding protein I mRNAs were increased by both topical retinaldehyde and all-trans retinoic acid. Whereas all-trans retinoic acid, 9-cis-retinoic acid, and 13-cis-retinoic acid were not detectable (limit 5 ng/g) in vehicle-treated skin, 0.05% retinaldehyde-treated skin contained 13 +/- 6.9 ng/g wet tissue of all-trans retinoic acid (mean +/- SD), 12.6 +/- 5.9 ng/g 13-cis-retinoic acid, and no 9-cis-retinoic acid. In contrast, 9-cis-retinoic acid was detectable in 0.05% of all-trans retinoic acid-treated skin, which also contained 25-fold more all-trans retinoic acid and 5-fold more 13-cis-retinoic acid than retinaldehyde-treated skin. Our results show that topical retinaldehyde is transformed in vivo into all-trans retinoic acid by mouse epidermis. The small amounts of ligand for retinoic acid nuclear receptors thus produced are sufficient to induce biologic effects similar to those resulting from the topical application of the ligand itself in much higher concentration.

Administration, Topical↗
PubMed1999

Antibacterial activity of retinaldehyde against Propionibacterium acnes.

BACKGROUND: Retinaldehyde has been shown to exert antibacterial activity in vitro. AIM: This study evaluates the effect of retinaldehyde on Propionibacterium acnes both in vivo and in vitro. METHODS: Microbial minimal inhibitory concentrations (MICs) of retinaldehyde and retinoic acid were determined on reference strains of P. acnes. In vivo activity of daily topical application of 0.05% retinaldehyde on the P. acnes density was evaluated after application in a single-blind randomised study. RESULTS: MICs of retinaldehyde were 4 mg/l for P. acnes No. CIP179 and CIP53119 and 8 mg/l for P. acnes No. CIP53117. In contrast, the MICs of retinoic acid were superior to 128 mg/l for these three strains. In vivo, retinaldehyde-treated areas displayed a significant decrease in counts of viable P. acnes as compared with the untreated areas with a median decrease of 10(2) log P. acnes/cm(2) after 2 weeks of daily application. Vehicle alone had no effect. CONCLUSION: The MIC of retinaldehyde against P. acnes suggests a direct antibacterial activity. Daily topical application of 0.05% retinaldehyde is associated with a clear reduction of the P. acnes density.

Administration, Topical↗
PubMed1998

Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment.

OBJECTIVE: We compared the activity and tolerance profile of a 0.05% retinaldehyde cream with a 0.05% retinoic acid cream and the retinaldehyde vehicle in patients with photodamaged skin of the face. METHODS: A silicone replica of the left crow's feet area was taken at baseline and at weeks 18 and 44. Skin replicas were then analyzed by means of an optical profilometry technique. Standard wrinkle and roughness features were then calculated and statistically analyzed. The tolerance profile of the test products was also clinically evaluated during the entire study. RESULTS: A total of 125 patients (40 in the retinoic acid group, 40 in the retinaldehyde group, and 45 in the vehicle group) were studied. At week 18, a significant reduction of the wrinkle and roughness features was observed with both retinaldehyde and retinoic acid. At week 44, a less pronounced reduction was demonstrated in both active groups. No statistically significant changes were observed with the retinaldehyde vehicle at any assessment point. A total of 135 patients constituted the safety population. Retinaldehyde was well tolerated during the entire study. In contrast, retinoic acid caused more local irritation, and affected compliance of the patients. CONCLUSION: Retinaldehyde was efficacious and well tolerated in patients with photodamage.

Adult↗
PubMed2004

Ultrasound imaging demonstration of the improvement of non-ablative laser remodeling by concomitant daily topical application of 0.05% retinaldehyde.

BACKGROUND: Retinaldehyde has been proven to be effective in the reduction of facial wrinkles. It has also demonstrated its usefulness when used before and after laser skin resurfacing. OBJECTIVE: A monocentric, comparative, randomized, double-blind study was performed to evaluate the efficacy of retinaldehyde versus excipient in combination with non-ablative laser remodeling treatment. METHODS: A total of 16 female patients (mean age 45 years) were enrolled for neck line and forehead rhytid treatment. They were randomly assigned into two groups. The RAL group (eight patients) was treated with a non-ablative laser (1540 nm Er:glass, 10 J/cm2 per pulse, three pulses, 2 Hz repetition rate, 4 mm spot, +5 degrees C cooling) and daily topical application of 0.05% retinaldehyde immediately after the first laser treatment and up to 3 months after the fifth treatment. The CTRL group (eight patients) was treated under similar conditions, except with a daily application of excipient. The thickness of the skin (forehead and neck) was measured by ultrasound imaging before the first treatment, 1 month after the third treatment, 1 month after the fifth treatment and 3 months after the fifth treatment. RESULTS: An increase of dermal thickness was observed for all patients treated by laser (groups RAL and CTRL) on the forehead and neck. However, the increase was greater for the RAL group (retinaldehyde) when compared with the CTRL group (excipient). Three months after the fifth treatment, the increase in dermal thickness (%) was, respectively, 5.27 versus 1.13 for the forehead and 10.54 versus 3.57 for the neck. The difference between groups was statistically significant in favor of the retinaldehyde group for the forehead (p<0.05) and of limited significance for the neck (p=0.08). CONCLUSION: When considering the reduced number of patients in each group, the statistical analysis demonstrates an evident advantage of using retinaldehyde versus excipient. This study demonstrates that irradiation with a 1540 nm Er:glass laser can be potentiated with concomitant daily topical application of 0.05% retinaldehyde.

Administration, Topical↗
PubMed1999

Metabolism of topical retinaldehyde.

OBJECTIVE: In order to circumvent the tolerance problems encountered with topical application of retinoic acid - a biologically active metabolite of vitamin A - we performed in various models a series of experiments aimed at assessing the bio-availability of topical retinaldehyde and its conversion into either retinoid stores or biologically active metabolites. METHODS: (i) (3)H-retinaldehyde was used as a precursor of either (3)H-retinol or (3)H-retinoic acid in human skin extracts and human cultured keratinocytes; (ii) the concentration of various retinoids resulting from the metabolism of topical retinaldehyde was determined in mouse skin and in human plasma. Retinoids were quantified by reverse-phase HPLC with UV detection. RESULTS: Human keratinocytes were shown to take up retinaldehyde and to convert it into retinoic acid in a differentiation-dependent manner, differentiating cells oxidising retinaldehyde more efficiently. In vivo models allowed us to demonstrate that retinaldehyde is taken up by the skin and is then predominantly converted into retinyl esters - a storage form of vitamin A - while delivering relatively low amounts of retinoic acid from a large reservoir. CONCLUSION: Topical retinaldehyde can be used as a precursor of endogenous retinoids, since it is converted into both storage and bio-active forms of vitamin A.

Administration, Topical↗
PubMed2002

A retrospective study of the effect of long-term topical application of retinaldehyde (0.05%) on the development of actinic keratosis.

BACKGROUND: The role of topical retinoids on photocarcinogenesis is still unclear. Retinaldehyde is a natural metabolite of vitamin A used as a cosmetic product. Its effect on actinic keratoses has not been studied to date. OBJECTIVE: To study the incidence of actinic keratoses during long-term application of retinaldehyde in order to evaluate a possible chemoprophylactic effect. METHODS: We conducted a retrospective study on 61 patients who had applied retinaldehyde on photoexposed body areas for a period ranging from 6 to 142 months. We counted the total number of actinic keratoses and cutaneous tumors that appeared over the time of exposure to retinaldehyde. RESULTS: The epidemiological characteristics of actinic keratoses were not modified by the application of retinaldehyde. Irregular application as compared to regular application of retinaldehyde was not associated with a change in the risk of actinic keratoses, suggesting that continuous use is not associated per se with a higher risk of actinic keratoses. CONCLUSION: With the statistical power limitation of this study, retinaldehyde applied alone does not appear to have prophylactic effects on the development of actinic keratoses. The design adopted is feasible to study the safety of cosmetic products applied for a long period of time.

Administration, Topical↗
PubMed2003

Genetic evidence that retinaldehyde dehydrogenase Raldh1 (Aldh1a1) functions downstream of alcohol dehydrogenase Adh1 in metabolism of retinol to retinoic acid.

Vitamin A (retinol) is a nutrient that is essential for developmental regulation but toxic in large amounts. Previous genetic studies have revealed that alcohol dehydrogenase Adh1 is required for efficient clearance of excess retinol to prevent toxicity, thus demonstrating that the mechanism involves oxidation of excess retinol to retinoic acid (RA). Whereas Adh1 plays a dominant role in the first step of the clearance pathway (oxidation of retinol to retinaldehyde), it is unknown what controls the second step (oxidation of retinaldehyde to RA). We now present genetic evidence that aldehyde dehydrogenase Aldh1a1, also known as retinaldehyde dehydrogenase Raldh1, plays a dominant role in the second step of retinol clearance in adult mice. Serum RA levels following a 50 mg/kg dose of retinol were reduced 72% in Raldh1-/- mice and 82% in Adh1-/- mice. This represented reductions in RA synthesis of 77-78% for each mutant after corrections for altered RA degradation in each. After retinol dosing, serum retinaldehyde was increased 2.5-fold in Raldh1-/- mice (indicating defective retinaldehyde clearance) and decreased 3-fold in Adh1-/- mice (indicating defective retinaldehyde synthesis). Serum retinol clearance following retinol administration was decreased 7% in Raldh1-/- mice and 69% in Adh1-/- mice. LD50 studies indicated a small increase in retinol toxicity in Raldh1-/- mice and a large increase in Adh1-/- mice. These observations demonstrate that Raldh1 functions downstream of Adh1 in the oxidative metabolism of excess retinol and that toxicity correlates primarily with accumulating retinol rather than retinaldehyde.

Alcohol Dehydrogenase↗
PubMed1999

Efficacy of topical 0.05% retinaldehyde in skin aging by ultrasound and rheological techniques.

BACKGROUND: The natural precursor of retinoic acid, i.e. retinaldehyde, has been proven to exert retinoid activities. AIM AND METHODS: The aim of this prospective instrument study was to determine the effect of topical retinaldehyde 0.05% on the physical properties of aging skin. This was performed using two devices, namely a high-resolution (70-80 microm) ultrasound scanner, which visualizes the thickness of both the epidermis and the dermis, and an echorheometer, which assesses the stiffness and elasticity of the skin by suction. In a 1-year study, 21 patients applied retinaldehyde cream 0.05% on the face, while another group of 19 volunteers were only treated with an emollient (control group). Epidermal and dermal thicknesses were measured on the forehead and temple, and stiffness and elasticity were measured on the forehead only. All the instrumental parameters were assessed at baseline and at the end of treatment. RESULTS: Compared to the control group, retinaldehyde treatment induced a significant increase in epidermal thickness of the temple, as well as in cutaneous elasticity (p < 0. 01). Similarly, retinaldehyde treatment tended to increase dermal thickness and reduce cutaneous stiffness, but no statistical difference could be observed between the two groups. CONCLUSION: Taken together, the results further suggest that retinaldehyde has counteracting effects on skin aging

Administration, Topical↗
PubMed2005

Mixing glycolic acid with retinaldehyde: RALGA, a technical achievement.

BACKGROUND: The use of retinaldehyde or glycolic acid was found to be effective in topical acne treatments. OBJECTIVE: The aim of this study was thus to take advantage of the possible synergistic effect between retinaldehyde and glycolic acid and to combine the latter in a single formulation, in other words, in an oil-in-water emulsion. METHODS: A certain number of critical parameters were taken into account when designing the formulation, i.e. solubility of retinaldehyde and glycolic acid, pH of the finished product and insufficient stability of retinaldehyde notably in the presence of water. Consequently, the oil components, which form the oily phase of the emulsion, were carefully selected according to the solubility of retinaldehyde. Moreover, we aimed at obtaining adequate emulsion stability so that a large amount of water could be used to make the hydroxy acid soluble. RESULTS AND CONCLUSION: The best retinaldehyde-glycolic acid (RALGA) formulation developed had a low pH (around 3.5) and, when stored at 40 degrees C, revealed a good stability. Finally, the antibacterial activity of this formulation was also tested in vitro against Propionibacterium acnes and showed antibacterial results after only 5 min of contact.

Chemistry, Pharmaceutical↗
PubMed1992

Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde.

Biotransformation of the biologically and pharmacologically important aldehydes, retinaldehyde and aldophosphamide, is mediated, in part, by NAD(P)-dependent aldehyde dehydrogenases catalyze the oxidation of the aldehydes to their respective acids, retinoic acid and carboxyphosphamide. Not known at the onset of this investigation was which of the several known human aldehyde dehydrogenases (ALDHs) catalyze these reactions. Thus, human liver aldehyde dehydrogenases were chromatographically resolved and the ability of each to catalyze the oxidation of retinaldehyde and aldophosphamide was assessed. Only one, namely ALDH-1, catalyzed the oxidation of retinaldehyde; the Km value was 0.3 microM. Three, namely ALDH-1, ALDH-2 and succinic semialdehyde dehydrogenase, catalyzed the oxidation of aldophosphamide; Km values were 52, 1193, and 560 microM, respectively. ALDH-4, ALDH-5 and betaine aldehyde dehydrogenase did not catalyze the oxidation of either aldophosphamide or retinaldehyde. ALDH-1 and succinic semialdehyde dehydrogenase accounted for 64 and 30%, respectively, of the total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide (160 microM) oxidation. ALDH-1-catalyzed oxidation of aldophosphamide was noncompetitively inhibited by chloral hydrate; the Ki value was 13 microM. ALDH-2- and succinic semialdehyde dehydrogenase-catalyzed oxidation of aldophosphamide was relatively insensitive to inhibition by chloral hydrate. These observations strongly suggest an important in vivo role for ALDH-1 in the catalysis of retinaldehyde and aldophosphamide biotransformation. Succinic semialdehyde dehydrogenase-catalyzed biotransformation of aldophosphamide may also be of some in vivo importance.

Adult↗
PubMed2003

Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid.

The ability of vitamin A (retinol) to control growth and development depends upon tissue-specific metabolism of retinol to retinoic acid (RA). RA then functions as a ligand for retinoid receptor signaling. Mouse genetic studies support a role for cytosolic alcohol dehydrogenases (ADH) in the first step (oxidation of retinol to retinaldehyde) and a role for cytosolic retinaldehyde dehydrogenases (RALDH) in the second step (oxidation of retinaldehyde to RA). Mice lacking ADH3 have reduced survival and a growth defect that can be rescued by dietary retinol supplementation, whereas the effect of a loss of ADH1 or ADH4 is noticed only in mice subjected to vitamin A excess or deficiency, respectively. Also, genetic deficiency of both ADH1 and ADH4 does not have additive effects, verifying separate roles for these enzymes in retinoid metabolism. As for the second step of RA synthesis, a null mutation of RALDH2 is embryonic lethal, eliminating most mesodermal RA synthesis, whereas loss of RALDH1 eliminates RA synthesis only in the embryonic dorsal retina with no obvious effect on development. Analysis of RA-rescued RALDH2 mutants has also revealed that RALDH3 and at least one additional enzyme produce RA tissue-specifically in embryos. Collectively, these genetic findings indicate that metabolism of retinol to retinaldehyde is not tissue-restricted as it is catalyzed by ubiquitously-expressed ADH3 (a low activity form) as well as by tissue-specifically expressed ADH1 and ADH4 (high activity forms). In contrast, further metabolism of retinaldehyde to RA is tissue-restricted as all enzymes identified are tissue-specific. An important concept to emerge is that selective expression of enzymes catalyzing the second step is what limits the tissues that can completely metabolize retinol to RA to initiate retinoid signaling.

Alcohol Dehydrogenase↗