Metabolism and biological potency of retro-retinyl acetate in the rat.
Ontology highlight
ABSTRACT:
SUBMITTER: John KV
PROVIDER: S-EPMC1270440 | biostudies-other | 1967 May
REPOSITORIES: biostudies-other
Similar Datasets
Project description:1. Treatment of 3-dehydroretinyl acetate with aqueous hydrobromic acid resulted in the formation of retro-3-dehydroretinyl acetate, which, on alkaline hydrolysis, gave the corresponding alcohol. 2. retro-3-Dehydroretinyl acetate was isomerized to 3-dehydrovitamin A when fed to vitamin A-deficient rats. 3. When retro-3-dehydroretinyl acetate was administered orally, it was hydrolysed to retro-3-dehydroretinol in the rat intestine, isomerized to 3-dehydroretinol and esterified before being transported to the liver for storage. 4. When administered intraperitoneally, both 3-dehydrovitamin A and retro-3-dehydrovitamin A were accumulated in liver and other tissues, whereas after enterectomy 3-dehydrovitamin A was not detected anywhere in the body. 5. The small intestine was shown to be the major site of conversion of retro-3-dehydrovitamin A into 3-dehydrovitamin A. 6. The extent of conversion of retro-3-dehydroretinyl acetate into 3-dehydrovitamin A was much smaller than that of the conversion of retro-retinyl acetate into vitamin A. 7. The biological potency of retro-3-dehydroretinyl acetate, determined by the rat-growth assay, was 2.6% of that all-trans-retinyl acetate, when given orally.
| S-EPMC1186787 | biostudies-other
Project description:1. The metabolism of 5,6-monoepoxyvitamin A aldehyde in the rat was found to be identical with that of vitamin A aldehyde. It promptly alleviated all the symptoms of vitamin A deficiency and promoted the growth of the vitamin A-deficient rats. 2. When administered orally, 5,6-monoepoxyvitamin A aldehyde was reduced to the corresponding alcohol in the intestine and esterified before being transported to the liver for storage. 3. 5,6-Monoepoxyvitamin A aldehyde was not converted into the furanoid form, 5,8-monoepoxyvitamin A aldehyde, during passage through the stomach. 4. Intraperitoneal administration of 5,6-monoepoxyvitamin A aldehyde led to the accumulation of 5,6-monoepoxyvitamin A in the liver and other tissues. Subcutaneous administration of this compound alleviated all the symptoms of vitamin A deficiency. 5. The small intestine is the major, if not the only, site for the metabolic reduction of 5,6-monoepoxyvitamin A aldehyde and its subsequent esterification. 6. It was demonstrated that the rat possesses the necessary enzymes for the reduction and oxidation of 5,6-monoepoxyvitamin A aldehyde to the corresponding alcohol and acid as well as the esterification of 5,6-monoepoxyvitamin A alcohol to its palmitate. These metabolic conversions were shown to be as efficient as those of vitamin A aldehyde and alcohol. 7. 5,6-Monoepoxyvitamin A aldehyde possesses a biological potency 108% that of all-trans vitamin A acetate. 8. A new visual pigment with lambda(max.) 480mmu, along with natural rhodopsin, was isolated from the retinas of rats maintained on 5,6-monoepoxyvitamin A aldehyde. 9. Oral administration of 5,8-monoepoxyvitamin A aldehyde to vitamin A-deficient rats led to the accumulation of 5,8-monoepoxyvitamin A in the liver and other tissues. Enzymic reduction and oxidation of 5,8-monoepoxyvitamin A aldehyde to its alcohol and acid, as well as the esterification of the alcohol, were demonstrated.
| S-EPMC1215173 | biostudies-other
Project description:PurposeMice lacking retinal pigment epithelium-specific 65-kDa protein (RPE65) develop retinopathy and blindness resembling Leber congenital amaurosis. Effects of 9-cis-retinyl acetate (9-cis-R-Ac) on visual function and retinopathy progression were tested in Rpe65(-/-) mice.MethodsYoung C57Bl/6 mice were given 9-cis-R-Ac in each of four different oil-based vehicle solutions by gastric gavage to identify the vehicle most suitable for drug delivery by measuring retinoid levels in plasma. Then doses of 9-cis-R-Ac ranging from 1 to 100 mg/kg were administered to 5- to 12-week-old Rpe65(-/-) mice by different treatment regimens, including single doses and either intermittent or daily doses for various periods up to 8 weeks. Retinoid effects on visual function were evaluated by electroretinography, retinoid analyses, histologic methods, and vision-dependent behavioral testing.ResultsSoybean oil vehicle provided the highest 9-cis-R-Ac metabolite levels in plasma. Single doses of 9-cis-R-Ac (6.25-50 mg/kg) provided significant dose-dependent improvement in electroretinographic responses. Well-tolerated daily doses (1-12.5 mg/kg) for 2 weeks induced remarkable improvement of retinal function. Significant dose-dependent improvement of electroretinographic responses was observed 6 days after administration of 9-cis-R-Ac daily for 3 days at 1 to 12.5 mg/kg. Mice given either daily or intermittent 9-cis-R-Ac treatment at 1 and 4 mg/kg and evaluated 8 weeks later displayed dose-dependent improvement of retinal function and morphology, whereas retinal function deteriorated in control animals. Treated mice also performed better than control animals in vision-dependent behavioral tests.ConclusionsTreatment with 9-cis-R-Ac improves visual function and preserves retinal morphology in Rpe65(-/-) mice.
| S-EPMC2764364 | biostudies-literature
Project description:The compound 9-cis-retinyl acetate (9-cis-RAc) is a precursor to 9-cis-retinal, which has potential application in the treatment of some hereditary diseases of the retina. An attractive synthetic route to 9-cis-RAc is based on the photoisomerization reaction of the readily available all-trans-RAc. In the present study, we examine the mechanism of the photoisomerization reaction with the use of state-of-the-art electronic structure calculations for two polyenic model compounds: tEtEt-octatetraene and tEtEtEc-2,6-dimethyl-1,3,5,7,9-decapentaene. The occurrence of photoisomerization is attributed to a chain-kinking mechanism, whereby a series of S1/S0 conical intersections associated with kinking deformations at different positions along the polyenic chain mediate internal conversion to the S0 state, and subsequent isomerization around one of the double bonds. Two other possible photoisomerization mechanisms are taken into account, but they are rejected as incompatible with simulation results and/or the available spectroscopic data.
| S-EPMC8488936 | biostudies-literature
Project description:1. Retinyl methyl ether was converted into vitamin A in vitamin A-deficient rats regardless of whether administered by oral, intraperitoneal, intramuscular or subcutaneous route; intramuscular administration seemed to be the best for conversion as well as storage. 2. Significantly, unchanged retinyl methyl ether was also found in the liver after oral administration but not after administration by other routes. 3. Oral administration of 1mg of retinyl methyl ether led to a progressive increase in liver vitamin A with time reaching a value of 16% of administered dose after 24h. No retinyl methyl ether was detectable in liver at any time-interval in this experiment. 4. Conversely, oral administration of 4mg of retinyl methyl ether/day for 4 days led to the accumulation of 25% of the dose as unchanged retinyl methyl ether in the liver 1 day after the last dose; however, it was gradually but completely converted into vitamin A over a period of 18 days. 5. The significance of these findings with special reference to the fundamental metabolism of vitamin A, the site of conversion of retinyl methyl ether into vitamin A, the relative efficiency of various routes of administration and its biological activity are discussed.
| S-EPMC1176798 | biostudies-other
Project description:Long-term effects of treatment with 9-cis-retinyl acetate (9-cis-R-Ac), an artificial retinoid prodrug, were tested on changes in rod and cone visual functions in mice.The acetyl ester of the functional geometric chromophore 9-cis-retinal was delivered by oral gavage to C57BL/6 female mice. In initial experiments, 10-month-old mice were used for the single treatment with 9-cis-R-Ac or the control vehicle. In long-term experiments, 4-month-old mice were treated with 9-cis-R-Ac monthly for 6 and 10 months. Photoreceptor status was evaluated by various electroretinographic (ERG) techniques, retinoid analyses, and retinal morphology. Opsin, the predicted target of oxidized 9-cis-R-Ac, was purified and its chromophore was characterized.Age-related changes observed in vehicle-treated mice at 10 months of age, compared with those in 4-month-old mice, included a progressive decline in ERG responses, such as a decreased rate of dark adaptation and a lowered rhodopsin/opsin ratio. Administration of 9-cis-R-Ac increased the rhodopsin regeneration ratio, and improved ERG responses and dark adaptation. Compared with vehicle-treated control animals, 10- and 14-month-old mice treated monthly with 9-cis-R-Ac for 6 or 10 months exhibited improved dark adaptation. In 14-month-old mice treated monthly, changes in the expression of retina-specific genes in the eye were detected by mRNA expression profiling, but no significant effects in gene expression were detected in the liver and kidney.Deteriorating photoreceptor function documented in mice at 10 and 14 versus 4 months of age was improved significantly by long-term, monthly administration of 9-cis-R-Ac. These findings suggest a potential therapeutic approach to prevent age-related retinal dysfunction.
| S-EPMC2615069 | biostudies-literature
Project description:Acetate kinase (ACK) (EC no: 2.7.2.1) interconverts acetyl-phosphate and acetate to either catabolize or synthesize acetyl-CoA dependent on the metabolic requirement. Among all ACK entries available in UniProt, we found that around 45% are multiple ACKs in some organisms including more than 300 species but surprisingly, little work has been done to clarify whether this has any significance. In an attempt to gain further insight we have studied the two ACKs (AckA1, AckA2) encoded by two neighboring genes conserved in Lactococcus lactis (L. lactis) by analyzing protein sequences, characterizing transcription structure, determining enzyme characteristics and effect on growth physiology. The results show that the two ACKs are most likely individually transcribed. AckA1 has a much higher turnover number and AckA2 has a much higher affinity for acetate in vitro. Consistently, growth experiments of mutant strains reveal that AckA1 has a higher capacity for acetate production which allows faster growth in an environment with high acetate concentration. Meanwhile, AckA2 is important for fast acetate-dependent growth at low concentration of acetate. The results demonstrate that the two ACKs have complementary physiological roles in L. lactis to maintain a robust acetate metabolism for fast growth at different extracellular acetate concentrations. The existence of ACK isozymes may reflect a common evolutionary strategy in bacteria in an environment with varying concentrations of acetate.
| S-EPMC3956926 | biostudies-literature
Project description:During aerobic growth on glucose, Escherichia coli excretes acetate, a mechanism called "overflow metabolism." At high concentrations, the secreted acetate inhibits growth. Several mechanisms have been proposed for explaining this phenomenon, but a thorough analysis is hampered by the diversity of experimental conditions and strains used in these studies. Here, we describe the construction of a set of isogenic strains that remove different parts of the metabolic network involved in acetate metabolism. Analysis of these strains reveals that (i) high concentrations of acetate in the medium inhibit growth without significantly perturbing central metabolism; (ii) growth inhibition persists even when acetate assimilation is completely blocked; and (iii) regulatory interactions mediated by acetyl-phosphate play a small but significant role in growth inhibition by acetate. The major contribution to growth inhibition by acetate may originate in systemic effects like the uncoupling effect of organic acids or the perturbation of the anion composition of the cell, as previously proposed. Our data suggest, however, that under the conditions considered here, the uncoupling effect plays only a limited role.IMPORTANCE High concentrations of organic acids such as acetate inhibit growth of Escherichia coli and other bacteria. This phenomenon is of interest for understanding bacterial physiology but is also of practical relevance. Growth inhibition by organic acids underlies food preservation and causes problems during high-density fermentation in biotechnology. What causes this phenomenon? Classical explanations invoke the uncoupling effect of acetate and the establishment of an anion imbalance. Here, we propose and investigate an alternative hypothesis: the perturbation of acetate metabolism due to the inflow of excess acetate. We find that this perturbation accounts for 20% of the growth-inhibitory effect through a modification of the acetyl phosphate concentration. Moreover, we argue that our observations are not expected based on uncoupling alone.
| S-EPMC6560135 | biostudies-literature
Project description:Brain uptake of [(14)C]acetate has been reported to be a useful marker of astrocytic energy metabolism. In addition to uptake values, the rate of radiolabeled acetate washout from the brain appears to reflect CO2 exhaustion and oxygen consumption in astrocytes. We measured the time-radioactivity curves of benzyl [1-(14)C]acetate ([1-(14)C]BA), a lipophilic probe of [1-(14)C]acetate, and compared it with that of benzyl [2-(14)C]acetate ([2-(14)C]BA) in rat brains. The highest brain uptake was observed immediately after injecting either [1-(14)C]BA or [2-(14)C]BA, and both subsequently disappeared from the brain in a single-exponential manner. Estimated [1-(14)C]BA washout rates in the cerebral cortex and cerebellum were higher than those of [2-(14)C]BA. These results suggested that [1-(14)C]BA could be a useful probe for estimating the astrocytic oxidative metabolism. The [1-(14)C]BA washout rate in the cerebral cortex of immature rats was lower than that of mature rats. An autoradiographic study showed that the washout rates of [1-(14)C]BA from the rat brains of a lithium-pilocarpine-induced status epilepticus model were not significantly different from the values in control rat brains except for the medial septal nucleus. These results implied that the enhancement of amino acid turnover rate rather than astrocytic oxidative metabolism was increased in status epilepticus.
| S-EPMC4759666 | biostudies-literature
Project description:Megestrol acetate is metabolized by homogenates of rat adrenal glands to three more polar metabolites Y(2), Y(3) and Y(4). Their structures were investigated by microchemical reactions, paper chromatography, and ultraviolet and infrared spectroscopy. Metabolite Y(3) was identified as 17alpha-acetoxy-11beta-hydroxy-6-methyl-pregna-4,6-diene-3,20-dione, its oxidation product being identical with authentic 17alpha-acetoxy-6-methylpregna-4,6-diene-3,11,20-trione. It is suggested that metabolite Y(2) is 17,18-dihydroxy-6-methylpregna-4,6-diene-3,20-dione and that it also exists in the form of an alpha-ketol formed between the 18-hydroxyl and 20-oxo groups. Metabolite Y(4) is probably a tautomeric form of metabolite Y(2) as they were partially interconverted on chromatography and also have similar properties.
| S-EPMC1186760 | biostudies-other