Retinoic Acid Formation Research Articles

Feedback regulation of retinaldehyde reductase DHRS3, a critical determinant of retinoic acid homeostasis.

Retinoic acid is crucial for vertebrate embryogenesis, influencing anterior-posterior patterning and organogenesis through its interaction with nuclear hormone receptors comprising heterodimers of retinoic acid receptors (RARα, β, or γ) and retinoid X receptors (RXRα, β, or γ). Tissue retinoic acid levels are tightly regulated since both its excess and deficiency are deleterious. Dehydrogenase/reductase 3 (DHRS3) plays a critical role in this regulation by converting retinaldehyde to retinol, preventing excessive retinoic acid formation. Mutations in DHRS3 can result in embryonic lethality and congenital defects. This study shows that mouse Dhrs3 expression is responsive to vitamin A status and is directly regulated by the RAR/RXR complex through cis-regulatory elements. This highlights a negative feedback mechanism that ensures retinoic acid homeostasis.

Loss of Cell-Cell Contact Inhibits Cellular Differentiation of α-Catenin Knock Out P19 Embryonal Carcinoma Cells and Their Colonization into the Developing Mouse Embryos.

Cadherin-catenin cell-cell adhesion complexes, composed of cadherin, β-catenin or plakoglobin, and α-catenin (α-cat) molecules, are crucial for maintaining cell-cell contact and are commonly referred to as "adherens junctions (AJs)." Inactivating this system leads to loss of cell-cell contact and developmental arrest in early embryos. However, it remains unclear whether the loss of cell-cell contact affects the differentiation of embryonic cells. In this study, we explored the use of a murine embryonal carcinoma cell line, P19, as an in vitro model for early embryogenesis. P19 cells easily form embryoid bodies (EBs) and are susceptible to cellular differentiation in response to retinoic acid (RA) and teratoma formation. Using CRISPR/Cas9 technology to disrupt the endogenous α-cat gene in P19 cells, we generated α-cat knockout (KO) cells that exhibited a loss of cell-cell contact. When cultivated on non-coated dishes, these α-cat KO cells formed EBs, but their structures were labile. In the RA-containing medium, the α-cat KO EBs failed to produce differentiated cells on their outer layer and continued to express SSEA-1, an antigen specific to pluripotent cells. Teratoma formation assays revealed an absence of overt differentiated cells in tumors derived from α-cat KO P19 cells. Aggregation assays revealed the inability of the KO cells to colonize into the zona pellucida-denuded 8-cell embryos. These findings suggest that the AJs are essential for promoting the early stages of cellular differentiation and for the colonization of early-developing embryos.

LX-2 Stellate Cells Are a Model System for Investigating the Regulation of Hepatic Vitamin A Metabolism and Respond to Tumor Necrosis Factor α and Interleukin 1β.

Hepatic stellate cells (HSCs) are the major site of vitamin A (retinol) esterification and subsequent storage as retinyl esters within lipid droplets. However, retinyl esters become depleted in many pathophysiological states, including acute and chronic liver injuries. Recently, using a liver slice culture system as a model of acute liver injury and fibrogenesis, a time-dependent increase and decrease in the apparent formation of the bioactive retinoid all-trans-retinoic acid (atRA) and retinyl palmitate was measured, respectively. This coincided with temporal changes in the gene expression of retinoid-metabolizing enzymes and binding proteins, that preceded HSC activation. However, the underlying mechanisms that promote early changes in retinoid metabolism remain unresolved. We hypothesized that LX-2 cells could be applied to investigate differences in quiescent and activated HSC retinoid metabolism. We demonstrate that the hypermetabolic state of activated stellate cells relative to quiescent stellate cells may be attributed to induction of STRA6, RBP4, and CYP26A1, thereby reducing intracellular concentrations of atRA. We further hypothesized that paracrine and autocrine cytokine signaling regulates HSC vitamin A metabolism in both quiescent and activated cells. In quiescent cells, tumor necrosis factor α dose-dependently downregulated LRAT and CRBP1 mRNA, with EC50 values of 30-50 pg/mL. Likewise, interleukin-1β decreased LRAT and CRBP1 gene expression but with less potency. In activated stellate cells, multiple enzymes were downregulated, suggesting that the full effects of altered hepatic vitamin A metabolism in chronic conditions require both paracrine and autocrine signaling events. Further, this study suggests the potential for cell type-specific autocrine effects in hepatic retinoid signaling. SIGNIFICANCE STATEMENT: HSCs are the major site of vitamin A storage and important determinants of retinol metabolism during liver fibrogenesis. Here, two LX-2 culture methods were applied as models of hepatic retinoid metabolism to demonstrate the effects of activation status and dose-dependent cytokine exposure on the expression of genes involved in retinoid metabolism. This study suggests that compared to quiescent cells, activated HSCs are hypermetabolic and have reduced apparent formation of retinoic acid, which may alter downstream retinoic acid signaling.

Retinoic acid core-shell lipoplexes for the treatment of colorectal cancer

The use of retinoic acid restricts the application in cancer using oral and intravenous drug delivery systems due to rapid decrease in plasma concentration. Moreover, low aqueous solubility and topical irritation limits the usage of retinoic acid in clinical studies. DNA, a non-viral vector stimulates the immune system against the cancerous cell by inhibiting the growth of tumour cell. The aim of the present research work was to formulate lipid-complexed with DNA using cationic lipid in the form of lipoplexes of retinoic acid on colorectal cancer cell lines. Lipoplexes are lipid-based systems with DNA attached to the cationic branch of the liposomes for easy and faster penetration inside the cell. Lipoplexes were prepared by film-hydration method and followed by complexation with DNA in presence of retinoic acid. The lipoplexes were characterized by surface morphology, surface charge, % drug encapsulation, in-vitro release profile and stability studies. Particle size of the lipoplexes of retinoic acid was found to be in the range of 306.12 ± 1.23–526.4 ± 4.25 nm. The smaller particle size and higher zeta potential indicated better stability of the formulations due to the development of more surface resistance for aggregation. The encapsulation efficiency was found to be 79.46 ± 2.12 % due to the complex formation of lipophilic retinoic acid and the lipid nature of liposomes. The in-vitro release study of retinoic acid from lipoplex network was found to be 78.56 ± 2.58 % with the first-order controlled release pattern for 24 h. Therefore, lipoplex formulation showed a novel approach for the delivery of retinoic acid in colorectal cancer for site-specific action.

Indole-3-carbinol, a plant nutrient and AhR-Ligand precursor, supports oral tolerance against OVA and improves peanut allergy symptoms in mice.

In general, dietary antigens are tolerated by the gut associated immune system. Impairment of this so-called oral tolerance is a serious health risk. We have previously shown that activation of the ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) by the environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects both oral tolerance and food allergy. In this study, we determine whether a common plant-derived, dietary AhR-ligand modulates oral tolerance as well. We therefore fed mice with indole-3-carbinole (I3C), an AhR ligand that is abundant in cruciferous plants. We show that several I3C metabolites were detectable in the serum after feeding, including the high-affinity ligand 3,3´-diindolylmethane (DIM). I3C feeding robustly induced the AhR-target gene CYP4501A1 in the intestine; I3C feeding also induced the aldh1 gene, whose product catalyzes the formation of retinoic acid (RA), an inducer of regulatory T cells. We then measured parameters indicating oral tolerance and severity of peanut-induced food allergy. In contrast to the tolerance-breaking effect of TCDD, feeding mice with chow containing 2 g/kg I3C lowered the serum anti-ovalbumin IgG1 response in an experimental oral tolerance protocol. Moreover, I3C feeding attenuated symptoms of peanut allergy. In conclusion, the dietary compound I3C can positively influence a vital immune function of the gut.

A RALDH-like enzyme involved in Fusarium verticillioides development

Retinaldehyde dehydrogenases (RALDHs) convert retinal to retinoic acid, an important chordate morphogen. Retinal also occurs in some fungi, such as Fusarium and Ustilago spp., evidenced by the presence of rhodopsins and β-carotene cleaving, retinal-forming dioxygenases. Based on the assumption that retinoic acid may also be formed in fungi, we searched the Fusarium protein databases for RALDHs homologs, focusing on Fusarium verticillioides. Using crude lysates of Escherichia coli cells expressing the corresponding cDNAs, we checked the capability of best matches to convert retinal into retinoic acid in vitro. Thereby, we identified an aldehyde dehydrogenase, termed CarY, as a retinoic acid-forming enzyme, an activity that was also exerted by purified CarY. Targeted mutation of the carY gene in F. verticillioides resulted in alterations of mycelia development and conidia morphology in agar cultures, and reduced capacity to produce perithecia as a female in sexual crosses. Complementation of the mutant with a wild-type carY allele demonstrated that these alterations are caused by the lackof CarY. However, retinoic acid could not be detected by LC–MS analysis either in the wild type or the complemented carY strain in vivo, making elusive the connection between CarY enzymatic activity and retinoic acid formation in the fungus.

Nmnat1-Rbp7 Is a Conserved Fusion-Protein That Combines NAD+ Catalysis of Nmnat1 with Subcellular Localization of Rbp7.

Retinol binding proteins (Rbps) are known as carriers for transport and targeting of retinoids to their metabolizing enzymes. Rbps are also reported to function in regulating the homeostatic balance of retinoid metabolism, as their level of retinoid occupancy impacts the activities of retinoid metabolizing enzymes. Here we used zebrafish as a model to study rbp7a function and regulation. We find that early embryonic rbp7a expression is negatively regulated by the Nodal/FoxH1-signaling pathway and we show that Nodal/FoxH1 activity has the opposite effect on aldh1a2, which encodes the major enzyme for early embryonic retinoic acid production. The data are consistent with a Nodal-dependent coordination of the allocation of retinoid precursors to processing enzymes with the catalysis of retinoic acid formation. Further, we describe a novel nmnat1-rbp7 transcript encoding a fusion of Rbp7 and the NAD+ (Nicotinamide adenine dinucleotide) synthesizing enzyme Nmnat1. We show that nmnat1-rbp7 is conserved in fish, mouse and chicken, and that in zebrafish regulation of nmnat1-rbp7a is distinct from that of rbp7a and nmnat1. Injection experiments in zebrafish further revealed that Nmnat1-Rbp7a and Nmnat1 have similar NAD+ catalyzing activities but a different subcellular localization. HPLC measurements and protein localization analysis highlight Nmnat1-Rbp7a as the only known cytoplasmic and presumably endoplasmic reticulum (ER) specific NAD+ catalyzing enzyme. These studies, taken together with previously documented NAD+ dependent interaction of RBPs with ER-associated enzymes of retinal catalysis, implicate functions of this newly described NMNAT1-Rbp7 fusion protein in retinol oxidation.

The human testis as a model of retinoic acid formation (1064.10)

Retinoic acid (RA), the active form of vitamin A (retinol), is indispensable for maintaining many essential biological processes. RA formation depends on a complex network of enzymes. The rate limiting step is irreversible formation of RA by aldehyde dehydrogenase1A (ALDH1A1‐1A3). However, the specific roles, tissue expression, and localization of these enzymes are not well understood.While RA is necessary for spermatogenesis in animal models, the source of intratesticular RA is unknown. Sertoli cell specific ALDH1A knockouts have demonstrated intratesticular RA formation is required for male fertility. Due to the requirement for intratesticular RA formation and presence of mRNA for all three ALDH1A enzymes in the human testis, the human testis was chosen as a model of the biochemistry of RA formation.In order to model RA formation, a novel LC‐MS/MS based peptide quantification method was developed to quantify ALDH1A in a cohort of 18 men. Each ALDH1A concentration was used to predict the velocity of RA formation in each donor. The accuracy of our predictions was confirmed by measuring intrinsic RA formation and RA concentrations in the same samples. Additionally, weidentified a distinct localization pattern for ALDH1A enzymes in the human testis using immunohistochemistry.In conclusion, these novel techniques were successfully used to model RA formation in human testicular tissue. In the future, RA formation in other tissues can be investigated using the assays developed.Grant Funding Source: Supported by NIH/NICHD grant U54 HD042454 and TL1TR000422

Retinol oxidation to retinoic acid in human thyroid glandular cells

Retinoic acid is regarded as the retinol metabolite that controls proliferation and differentiation of epithelial cells. In the present study, we investigated the potential role of xanthine dehydrogenase (XDH) in retinoic acid biosynthesis in human thyroid glandular cells (HTGC). In particular, we observed that cellular retinoids binding proteins (CRBPs) are also implicated in the biosynthetic pathway leading to retinoic acid formation in primary cultures of HTGC, as we have already reported for human mammary epithelial cells (HMEC). After partial protein purification, the enzyme responsible for retinoic acid biosynthesis was identified and quantified as XDH by immunoassay, by its ability to oxidize xanthine to uric acid and its sensitivity to the inhibitory effect of oxypurinol. The evidence of XDH-driven formation of retinoic acid in HTGC cultures further corroborates the potential role of XDH in retinoic acid biosynthesis in the epithelia.

The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development

Oxidation of retinol via retinaldehyde results in the formation of the essential morphogen all-trans-retinoic acid (ATRA). Previous studies have identified critical roles in the regulation of embryonic ATRA levels for retinol, retinaldehyde, and ATRA-oxidizing enzymes; however, the contribution of retinaldehyde reductases to ATRA metabolism is not completely understood. Herein, we investigate the role of the retinaldehyde reductase Dhrs3 in embryonic retinoid metabolism using a Dhrs3-deficient mouse. Lack of DHRS3 leads to a 40% increase in the levels of ATRA and a 60% and 55% decrease in the levels of retinol and retinyl esters, respectively, in Dhrs3(-/-) embryos compared to wild-type littermates. Furthermore, accumulation of excess ATRA is accompanied by a compensatory 30-50% reduction in the expression of ATRA synthetic genes and a 120% increase in the expression of the ATRA catabolic enzyme Cyp26a1 in Dhrs3(-/-) embryos vs. controls. Excess ATRA also leads to alterations (40-80%) in the expression of several developmentally important ATRA target genes. Consequently, Dhrs3(-/-) embryos die late in gestation and display defects in cardiac outflow tract formation, atrial and ventricular septation, skeletal development, and palatogenesis. These data demonstrate that the reduction of retinaldehyde by DHRS3 is critical for preventing formation of excess ATRA during embryonic development.

Light and ocular immunity

Current scientific evidence suggests that the systemic immune response is affected by exposure to light. During the past century man has been exposed for the first time in evolution to light at night, as well as increasing ultraviolet radiation through depletion of the ozone layer in our atmosphere. These ecological changes have enhanced the impact of light on our systemic immune response. We will review the effect of light on the systemic immune response with particular emphasis on ocular immunity. Visible light is now recognized to be important in the maintenance of immune privilege within the eye; however, little is known about the mechanism through which this effect occurs. Recent studies suggest that the generation of regulatory T cells involved in immune privilege within the eye is dependent on retinoic acid formation by retinal pigment epithelial cells. Light is also important in modulation of multiple pathways including adjustment of circadian rhythm and production of vitamin D. Light regulates our biologic systems in many different ways. Its effect on the systemic immune response suggests that it is important in maintaining health, as well as in the induction of disease. A better understanding of the interaction of light with our biologic systems may allow new preventive measures to avoid disease and novel forms of treatment.

Enzymes of the AKR1B and AKR1C Subfamilies and Uterine Diseases

Endometrial and cervical cancers, uterine myoma, and endometriosis are very common uterine diseases. Worldwide, more than 800,000 women are affected annually by gynecological cancers, as a result of which, more than 360,000 die. During their reproductive age, about 70% of women develop uterine myomas and 10–15% suffer from endometriosis. Uterine diseases are associated with aberrant inflammatory responses and concomitant increased production of prostaglandins (PG). They are also related to decreased differentiation, due to low levels of protective progesterone and retinoic acid, and to enhanced proliferation, due to high local concentrations of estrogens. The pathogenesis of these diseases can thus be attributed to disturbed PG, estrogen, and retinoid metabolism and actions. Five human members of the aldo-keto reductase 1B (AKR1B) and 1C (AKR1C) superfamilies, i.e., AKR1B1, AKR1B10, AKR1C1, AKR1C2, and AKR1C3, have roles in these processes and can thus be implicated in uterine diseases. AKR1B1 and AKR1C3 catalyze the formation of PGF2α, which stimulates cell proliferation. AKR1C3 converts PGD2 to 9α,11β-PGF2, and thus counteracts the formation of 15-deoxy-PGJ2, which can activate pro-apoptotic peroxisome-proliferator-activated receptor γ. AKR1B10 catalyzes the reduction of retinal to retinol, and thus lessens the formation of retinoic acid, with potential pro-differentiating actions. The AKR1C1–AKR1C3 enzymes also act as 17-keto- and 20-ketosteroid reductases to varying extents, and are implicated in increased estradiol and decreased progesterone levels. This review comprises an introduction to uterine diseases and AKR1B and AKR1C enzymes, followed by an overview of the current literature on the AKR1B and AKR1C expression in the uterus and in uterine diseases. The potential implications of the AKR1B and AKR1C enzymes in the pathophysiologies are then discussed, followed by conclusions and future perspectives.

Detection of the expression of aldehyde deshydrogenase 1A2 (ALDH1A2) in cumulus cells (CC) By differential gene expression analysis: Implications for maturation

ALDH1A2 catalyzes the formation of retinoic acid (RA). RA is important during the formation of primordial follicles in humans and oocyte cytoplasmic maturation in the bovine. Expressions of RA receptors have been found in CC and higher RA concentration are found in follicular fluids of dominants follicles which was correlated with estradiol (E2) concentration. Objective

Lemon Grass (Cymbopogon citratus) Ameliorates Murine Spontaneous Ileitis by Decreasing Lymphocyte Recruitment to the Inflamed Intestine

Aberrant leukocyte migration has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Lemon grass is a natural herb that contains citral, which suppresses lymphocyte expression of gut homing molecules by inhibiting retinoic acid formation. We therefore hypothesized that lemon grass intake could ameliorate excess migration of leukocytes to the inflamed intestine in chronic ileitis. Migration of fluorescence-labeled T cells to microvessels in the ileal mucosa of SAMP1/Yit mice was monitored using intravital microscopy. In some mice, lemon grass solution was administered for two weeks. For evaluation of the effects on chronic ileitis, mice were treated with lemon grass for 26 weeks. Surface expression of beta7 and CCR9 on T lymphocytes was stronger in SAMP1/Yit mice than in AKR/J mice. Lemon grass treatment attenuated the surface expression of beta7-integrin and CCR9. The number of adherent lymphocytes to microvessels in chronic inflamed ileum was significantly few when lymphocytes were isolated from lemon grass treated mice. Long-term lemon grass treatment improved ileitis in SAMP1/Yit mice, which was assessed by body weight, histological changes and the infiltration of beta7-positive cells. Lemon grass ameliorated ileitis through decreasing lymphocyte migration by inhibiting beta7-expression, suggesting its therapeutic usefulness for IBD.

The regulation of retinoic acid formation.

Rat liver microsomal as well as cytosolic retinol dehydrogenases from cellular retinal-binding protein (CRBP)-retinal from CRBP-retinol. A cytosolic dehydrogenase transforms retinal into retinoic acid. Apo-CRBP and ethanol inhibit the cytosolic but not the microsomal retinol dehydrogenase, the latter being the primary enzyme in the rate-limiting step in retinoic acid synthesis.

Uncompetitive Inhibition of Xenopus laevis Aldehyde Dehydrogenase 1A1 by Divalent Cations

Aldehyde dehydrogenases (ALDHs) convert aldehydes into their corresponding carboxylic acids. ALDH1A1, also known as ALDH class 1 (ALDH1) or retinaldehyde dehydrogenase (RALDH1), prefers retinal to acetaldehyde as a substrate. To investigate the effects of divalent cations on the dehydrogenase activity of Xenopus laevis ALDH1A1, the formation of acetate and retinoic acid from acetaldehyde and retinal, respectively, was investigated in the presence of Ca2+, Mg2+, Mn2+ or Zn2+. All divalent cations tested inhibited the oxidation of acetaldehyde and retinal by ALDH1A1. When acetaldehyde was used as a substrate, the 50% inhibitory concentrations (IC50) were 10, 24, 35 and 220 microM for Zn2+, Mn2+, Mg2+ and Ca2+, respectively. Kinetic studies of ALDH1A1 dehydrogenase activity in the presence or absence of each cation revealed that the inhibition mode by cations was uncompetitive against acetaldehyde, retinal, and NAD+, and that their inhibitory potencies were greater against acetaldehyde than retinal. It was concluded that the divalent cations inhibited X. laevis ALDH1A1 activity in a substrate-dependent manner by affecting a step of the dehydrogenase reaction that occurred after the formation of the ternary complex of the enzyme, substrate, and coenzyme.

Acetaldehyde inhibits the formation of retinoic acid from retinal in the rat esophagus

Objective. It has already been demonstrated that the rat esophagus produces retinoic acid from retinol. In this study, this process is further characterized and the effect of acetaldehyde examined to elucidate the possible mechanisms behind the epidemiological evidence that the incidence of esophageal cancer is higher in alcoholics. Material and methods. Rat esophageal samples were incubated with all-trans retinal and newly formed all-trans retinoic acid (ATRA) was quantified using high-performance liquid chromatography (HPLC). Furthermore, β-nicotinamide adenine dinucleotide (NAD)-dependent acetaldehyde oxidation by the rat esophagus was examined by tracing NAD reduction using a spectrophotometer. Results. Rat esophageal samples produced ATRA from all-trans retinal in a NAD-dependent manner and the potential was significantly attenuated by phenetyl isothiocynate, an ALDH inhibitor, or acetaldehyde depending on the concentration used. Rat esophageal samples also oxidized acetaldehyde of various concentrations NAD dependently. The ATRA formation potential that was temporarily inhibited by acetaldehyde was recovered to the control level by dialysis when the specimen was incubated with up to 50 µM of acetaldehyde. Conclusions. The rat esophagus produces retinoic acid from retinal. An ALDH isoform(s) is responsible for this process and physiological concentration of acetaldehyde hampers the process, probably in a competitive manner. Since the disturbance of retinoic acid supply has been implicated in carcinogenicity, this finding may, at least in part, explain the high incidence of esophageal cancer in alcoholics, especially in those with inactive ALDH 2 whose blood acetaldehyde levels become higher than those with active ALDH 2.

Retinoic acid formation from retinol in the human gastric mucosa: role of class IV alcohol dehydrogenase and its relevance to morphological changes

Alcohol dehydrogenase (ADH) participates in the formation of retinoic acid from retinol in various organs including the gastric mucosa. However, its clinical significance still remains to be clarified. In this study, we identified the ADH isoforms responsible for the retinoic acid formation among various ADH isoforms and examined associations among the ADH activities, the retinoic acid formation level, and morphological changes in the human gastric mucosa. Human gastric samples were endoscopically obtained from 67 male subjects. Morphological changes were assessed by the Sydney system and activities of class I, III, and IV ADH isoforms were determined in each specimen. In 26 cases, levels of all-trans retinoic acid (ATRA) formation from all-trans retinol were examined. Among activities of the three ADH isoforms, class IV ADH activity was solely associated with the ATRA formation level. This association was found even when subjects' age and Helicobacter pylori infection status were adjusted. As the degrees of inflammation, atrophy, and intestinal metaplasia increased, the class IV ADH activity as well as the potential for the ATRA formation decreased. Class IV ADH is a major enzyme in the retinoic acid supply in the human gastric mucosa, and the reduction of its activity was associated with decreasing retinoic acid supply and progression of inflammation, atrophy, and intestinal metaplasia in the gastric mucosa. In that retinoic acid is a key molecule for maintaining normal morphology, the reduction of class IV ADH activity may be involved in the pathogenesis of these morphological changes in the human gastric mucosa.

Nicotinamide Adenine Dinucleotide‐Dependent Retinoic Acid Formation From Retinol in the Human Gastric Mucosa: Inhibition by Ethanol, Acetaldehyde, and H2 Blockers

All‐trans retinoic acid formation from all‐trans retinol (vitamin A) in the human gastric mucosa was studied. When all‐trans retinol and the human gastric mucosa were incubated together, all‐trans retinoic acid was formed in the presence of nicotinamide adenine dinucleotide (NAD). When the NAD was not added, hardly any formation was observed. The formation of all‐trans retinoic acid tended to be attenuated by 10 mM ethanol. Moreover, it was significantly attenuated in a concentration‐dependent manner by ethanol at concentrations of 100 mM and above. Acetaldehyde at concentrations of 50 μM and above also significantly attenuated its formation in a concentration‐dependent manner. Some H2 blockers, which include ranitidine hydrochloride and cimetidine, significantly attenuated the formation of all‐trans retinoic acid, whereas famotidine failed to suppress it. There is an NAD‐dependent pathway by which all‐trans retinoic acid is produced from all‐trans retinol in the human gastric mucosa. Inhibitors of alcohol dehydrogenase, which include ethanol and some H2 blockers, and of aldehyde dehydrogenase, which include acetaldehyde, inhibit its production.

Nicotinamide adenine dinucleotide-dependent retinoic acid formation from retinol in the human gastric mucosa: inhibition by ethanol, acetaldehyde, and H2 blockers.

All-trans retinoic acid formation from all-trans retinol (vitamin A) in the human gastric mucosa was studied. When all-trans retinol and the human gastric mucosa were incubated together, all-trans retinoic acid was formed in the presence of nicotinamide adenine dinucleotide (NAD). When the NAD was not added, hardly any formation was observed. The formation of all-trans retinoic acid tended to be attenuated by 10 mM ethanol. Moreover, it was significantly attenuated in a concentration-dependent manner by ethanol at concentrations of 100 mM and above. Acetaldehyde at concentrations of 50 microM and above also significantly attenuated its formation in a concentration-dependent manner. Some H2 blockers, which include ranitidine hydrochloride and cimetidine, significantly attenuated the formation of all-trans retinoic acid, whereas famotidine failed to suppress it. There is an NAD-dependent pathway by which all-trans retinoic acid is produced from all-trans retinol in the human gastric mucosa. Inhibitors of alcohol dehydrogenase, which include ethanol and some H2 blockers, and of aldehyde dehydrogenase, which include acetaldehyde, inhibit its production.