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At least 19 recordsLinked to original sources
PubMed1998

Colocalization of 11-cis retinyl esters and retinyl ester hydrolase activity in retinal pigment epithelium plasma membrane.

PURPOSE: To identify the subcellular locale of 11-cis retinyl esters in bovine retinal pigment epithelium (RPE) and to characterize the enzymic mechanism responsible for liberation of 11-cis retinoids in this compartment. METHODS: Endoplasmic reticulum (ER)- enriched and plasma membrane (PM)-enriched protein fractions were prepared from bovine RPE microsomes using sequential discontinuous sucrose and Percoll gradient fractionation. Enzyme markers for ER (such as carboxylesterase), and PM (such as 5'-nucleotidase [5'-ND]; alkaline phosphatase [AP]; and ouabain-sensitive Na+,K+-ATPase [ATPase]) were used to identify the subfractions. Membrane-associated retinoids were quantified by high-performance liquid chromatography (HPLC) and retinyl ester hydrolase (REH) activities were determined by radiometric and chromatographic (HPLC) means. RESULTS: Chromatographic analyses of membrane-associated retinoids showed that 11-cis retinyl esters are localized mainly in PM-enriched fractions, whereas all-trans retinyl esters are associated predominantly with ER-enriched membranes; profiles of the distribution of 11-cis- and all-trans REH activities were consistent with the retinyl ester distribution. Further purification of the crude PM fraction yielded a fraction (P2) that was significantly enriched with 5'-ND (fivefold), ATPase (15-fold), AP (10-fold), and 11-cis retinyl ester hydrolase (11-cis REH; threefold) activities, but was relatively devoid of carboxylesterase and all-trans REH activities. Apparent kinetic constants (Km(app) and Vm(app)) for 11-cis REH activity in P2 were 18 microM and 1800 picomoles/min per mg, respectively. CONCLUSIONS: This is the first identification of an 11-cis-specific REH activity in RPE plasma membrane. Results from these studies demonstrate the capacity of RPE plasma membranes to accommodate and hydrolyze 11-cis retinyl esters. Plasma membrane storage and mobilization of 11-cis retinyl esters represents a novel compartmentalization of retinoid metabolism that is distinct from the sites where 11-cis retinoids are produced. The implication of these findings for present theories of visual chromophore biosynthesis are discussed.

5'-Nucleotidase↗
PubMed1995

Hepatic uptake and metabolism of chylomicron retinyl esters: probable role of plasma membrane/endosomal retinyl ester hydrolases.

Previous studies have indicated the presence of both neutral and acid, bile salt-independent retinyl ester hydrolases associated with plasma membrane and endosome fractions of rat liver homogenates. In the present studies, chylomicrons containing tritium-labeled retinyl esters were injected intravenously into rats in order to study the initial metabolism of retinyl esters during and after uptake into the liver. At various times after chylomicron injection, plasma was obtained and the liver was homogenized and subjected to analytical subcellular fractionation. Labeled retinyl esters were rapidly cleared from plasma (half-time approximately 10 min) and appeared in the liver. Within the liver, label first appeared in plasma membrane/endosomal fractions that were also enriched in both neutral and acid, bile salt-independent retinyl ester hydrolase activities. At no time were the labeled esters significantly associated with fractions enriched in lysosomes. Rather, it appeared that the labeled esters were hydrolyzed and/or transferred to fractions enriched in endoplasmic reticulum. These studies demonstrate the co-localization of newly delivered retinyl esters and bile salt-independent retinyl ester hydrolase enzyme activities and thus, suggest a probable role for these enzymes in the initial hepatic metabolism of chylomicron retinyl esters. This conclusion was further supported by the observation that plasma membrane/endosomal fractions were active in catalyzing the hydrolysis of chylomicron remnant retinyl esters in vitro.

Animals↗
PubMed1999

Intestinal absorption of dietary cholesteryl ester is decreased but retinyl ester absorption is normal in carboxyl ester lipase knockout mice.

Carboxyl ester lipase (CEL; EC 3.1.1.13) hydrolyzes cholesteryl esters and retinyl esters in vitro. In vivo, pancreatic CEL is thought to liberate cholesterol and retinol from their esters prior to absorption in the intestine. CEL is also a major lipase in the breast milk of many mammals, including humans and mice, and is thought to participate in the processing of triglycerides to provide energy for growth and development while the pancreas of the neonate matures. Other suggested roles for CEL include the direct facilitation of the intestinal absorption of free cholesterol and the modification of plasma lipoproteins. Mice with different CEL genotypes [wild type (WT), knockout (CELKO), heterozygote] were generated to study the functions of CEL in a physiological system. Mice grew and developed normally, independent of the CEL genotype of the pup or nursing mother. Consistent with this was the normal absorption of triglyceride in CELKO mice. The absorption of free cholesterol was also not significantly different between CELKO (87 +/- 26%, mean +/- SD) and WT littermates (76 +/- 10%). Compared to WT mice, however, CELKO mice absorbed only about 50% of the cholesterol provided as cholesteryl ester (CE). There was no evidence for the direct intestinal uptake of CE or for intestinal bacterial enzymes that hydrolyze it, suggesting that another enzyme besides CEL can hydrolyze dietary CE in mice. Surprisingly, CELKO and WT mice absorbed similar amounts of retinol provided as retinyl ester (RE). RE hydrolysis, however, was required for absorption, implying that CEL was not the responsible enzyme. The changes in plasma lipid and lipoprotein levels to diets with increasing lipid content were similar in mice of all three CEL genotypes. Overall, the data indicate that in the mouse, other enzymes besides CEL participate in the hydrolysis of dietary cholesteryl esters, retinyl esters, and triglycerides.

Animals↗
PubMed2002

Human melanomas of fibroblast and epithelial morphology differ widely in their ability to synthesize retinyl esters.

Reduced retinyl ester synthesis has been associated with several forms of cancer; we therefore proposed studying melanoma development from the perspective of this biochemical pathway. Cultures of human melanoma cells with fibroblastoid morphology showed negligible retinyl ester synthesis; in sharp contrast, those with epithelioid morphology were capable of retinol esterification. Further, isolated proliferating epidermal melanocytes (HFSC/2) esterified retinol, whereas proliferating normal skin fibroblasts (F:CCD-1121.Sk) did not. A primary site cutaneous melanoma and its metastatic match (both of epithelioid morphology) were capable of retinol esterification, while a matched fibroblastoid tumor pair did not synthesize retinyl esters; nevertheless, LRAT (lecithin:retinol acyltransferase) protein was found in microsomal fractions from all four tumors. A mutation screen in the LRAT coding region and adjacent intronic sequences revealed several novel mutations in these melanomas as well as in HFSC/2 and F:CCD-1121.Sk cells: a single nucleotide polymorphism in exon 1(37A-->G), a silent mutation in exon 2a (188 A-->G/186 G-->A), and an insertion in the 5'UTR (9-10insC). CRBP-1 basal expression was present in the HFSC/2, and in both sets of matched tumor pairs; however, steady-state levels in the fibroblastoid melanoma pair were one-third that found in the epithelioid matched tumor pair. Co-culture of human primary site epithelioid melanoma with proliferating normal human skin fibroblasts abrogated retinol esterification within 96 h and increased the expression of the active form of TGFbeta-1 by 2.4-fold. A concomitant 3.2-fold downregulation of CRBP-1 expression took place. This is the first study to (1) demonstrate an association between retinyl ester synthesis and cutaneous melanoma morphological phenotypes; (2) suggest the existence of a soluble, diffusible inhibitor of the retinol esterification pathway; (3) report the ability of the isolated, proliferating human epidermal melanocyte to esterify retinol; and (4) provide evidence of DNA variants in the coding region of LRAT.

Acyltransferases↗
PubMed1989

Relationship of vitamin A and vitamin E intake to fasting plasma retinol, retinol-binding protein, retinyl esters, carotene, alpha-tocopherol, and cholesterol among elderly people and young adults: increased plasma retinyl esters among vitamin A-supplement users.

We studied the relationships of supplemental and total vitamin A and supplemental vitamin E intake with fasting plasma biochemical indicators of vitamin A and vitamin E nutritional status among 562 healthy elderly people (aged 60-98 y) and 194 healthy young adult (aged 19-59 y) volunteers. All subjects were nonsmokers. For the young adults, plasma retinol was significantly greater in males than in females (p less than 0.01); retinol was not related to supplemental vitamin A intake for either group. Fasting plasma retinyl esters demonstrated a significant increase with vitamin A supplement use. For supplemental vitamin A intakes of 5001-10,000 IU/d, a 2.5-fold increase over nonusers in fasting plasma retinyl esters was observed for elderly people (p less than 0.05) and a 1.5-fold increase for young adults (p greater than 0.20). For elderly people, greater fasting plasma retinyl esters were associated with long-term vitamin A supplement use (greater than 5 y) and biochemical evidence of liver damage. Elderly people who take vitamin A supplements may be at increased risk for vitamin A overload.

Aged↗
PubMed1981

High-pressure liquid chromatography of fatty acid esters of retinol isomers. Analysis of retinyl esters stored in the eye.

We have synthesized the all-trans, 13-cis, 11-cis, and 9-cis retinyl esters of some or all of the following fatty acids: caprylic (8:0), capric (10:0), lauric (12:0), myristic (14:0), palmitic (16:0), stearic (18:0), arachidic (20:0), palmitoleic (16:1), oleic (18:1), linoleic (18:2), linolenic (18:3), arachidonic (20:4), and docosahexaenoic (22:6). Mixtures of these compounds were analyzed by high-pressure liquid chromatography on an Altex 100 chromatograph. This approach has enabled us to investigate and identify both the isomeric form and fatty acid basis of the retinyl esters present in rabbit and rat ocular tissues. Dark-adapted rabbits had 11-cis and all-trans retinyl esters, whereas light-adapted albino rats had only the all-trans isomer. The fatty acids utilized for esterification were almost wholly palmitic for the rabbit, whereas both stearic and palmitic were present in the rat esters. Rabbits are similar to frogs in that a large proportion (80%) of their ocular retinyl esters occurred in large, fluorescent oil droplets in the pigment epithelium. These are absent in rats.

Adaptation, Physiological↗
PubMed1983

Plasma lipoprotein retinoids after vitamin A feeding in normal man: minimal appearance of retinyl esters among low-density lipoproteins.

Retinyl esters have been thought to be carried solely by lipoproteins of intestinal origin (chylomicrons and their catabolic derivatives). Recent reports, however, have indicated that there may be significant transfer of retinyl esters from chylomicrons to low-density lipoproteins (LDL) in vitro, and that in other species, substantial amounts of retinyl esters may appear in LDL. Since in man lipoproteins of intestinal origin are not considered to contribute to a quantitatively significant extent to circulating LDL, we have examined this issue further. The distribution of retinol and retinyl esters within the plasma lipoproteins of eight normal human volunteers was measured following the ingestion of vitamin A along with a mixed meal. Retinyl esters appeared in the chylomicrons and very-low-density lipoproteins. Small amounts of retinyl esters were also detected in the intermediate- and low-density lipoprotein (LDL) classes. Estimates of the masses of retinyl esters, however, indicated that 5% or less of chylomicron retinyl esters appeared in the LDL. These observations are consistent with orderly chylomicron delipidation and provide further evidence that chylomicron-derived components do not contribute directly or to a quantitatively significant extent to circulating LDL.

Adult↗
PubMed2001

Determination of retinol and retinyl esters in human plasma by high-performance liquid chromatography with automated column switching and ultraviolet detection.

A HPLC method with automated column switching and UV detection is described for the simultaneous determination of retinol and major retinyl esters (retinyl palmitate, retinyl stearate, retinyl oleate and retinyl linoleate) in human plasma. Plasma (0.2 ml) was deproteinized by adding ethanol (1.5 ml) containing the internal standard retinyl propionate. Following centrifugation the supernatant was directly injected onto the pre-column packed with LiChrospher 100 RP-18 using 1.2% ammonium acetate-acetic acid-ethanol (80:1:20, v/v) as mobile phase. The elution strength of the ethanol containing sample solution was reduced by on-line supply of 1% ammonium acetate-acetic acid-ethanol (100:2:4, v/v). The retained retinol and retinyl esters were then transferred to the analytical column (Superspher 100 RP-18, endcapped) in the backflush mode and chromatographed under isocratic conditions using acetonitrile-methanol-ethanol-2-propanol (1:1:1:1, v/v) as mobile phase. Compounds of interest were detected at 325 nm. The method was linear in the range 2.5-2000 ng/ml with a limit of quantification for retinol and retinyl esters of 2.5 ng/ml. Mean recoveries from plasma were 93.4-96.5% for retinol (range 100-1000 ng/ml) and 92.7-96.0% for retinyl palmitate (range 5-1000 ng/ml). Inter-assay precision was < or =5.1% and < or =6.3% for retinol and retinyl palmitate, respectively. The method was successfully applied to more than 2000 human plasma samples from clinical studies. Endogenous levels of retinol and retinyl esters determined in female volunteers were in good accordance with published data.

Automation↗
PubMed1989

In vitro stimulation of rat liver retinyl ester hydrolase by ethanol.

Retinyl ester hydrolase (REH), the enzyme which converts retinyl esters to retinol, was partially characterized from whole liver homogenates of rats using an HPLC method with quantitation of retinol product. Optimal results were obtained by incubation of 1 mg of whole homogenate protein with 900 microM all-trans-retinyl palmitate and 275 mM 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate in a 0.1 M Tris-maleate buffer, pH 7.0, for 1 h at 37 degrees C. The enzyme assay proved to be sensitive and reproducible, with an interanimal coefficient of variation of 13% (n = 7). Because ethanol has been shown to mobilize vitamin A from the liver, we tested its effect on REH activity at several concentrations. In concentrations ranging from 0.01 to 0.5 M, ethanol added in vitro caused a concentration related increase in REH activity (from 20 to 86% above baseline activity). This increase was specific to ethanol as acetaldehyde, 1-propanol, and t-butanol either did not change or significantly decreased REH activity over the range of concentrations tested. The range of concentrations of ethanol causing stimulation in our assays was within the range of concentrations seen in the blood of rats after acute ethanol ingestion. Stimulation of REH activity could explain, in part, the well-known effects of ethanol on mobilization of vitamin A from liver stores.

Acetaldehyde↗
PubMed2005

The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters.

The final step of triacylglycerol biosynthesis is catalyzed by acyl CoA:diacylglycerol acyltransferase (DGAT) enzymes. The two known DGATs, DGAT1 and DGAT2, are encoded by unrelated genes. Although both DGAT1 and DGAT2 knockout mice have reduced tissue triacylglycerol contents, they have disparate phenotypes, prompting us to investigate whether the two enzymes have unrecognized functional differences. We now report that DGAT1 exhibits additional acyltransferase activities in vitro, including those of acyl CoA:monoacylglycerol acyltransferase (MGAT), wax monoester and wax diester synthases, and acyl CoA:retinol acyltransferase (ARAT), which catalyze the synthesis of diacylglycerols, wax esters, and retinyl esters, respectively. These activities were demonstrated in in vitro assays with membranes from insect cells or homogenates from COS7 cells overexpressing DGAT1. Wax synthase and ARAT activities were also demonstrated in intact COS7 cells expressing DGAT1. Additionally, cells and tissues from DGAT1-deficient mice exhibited reduced ARAT activity, and the mice had increased levels of unesterified retinol in their livers on a high-retinol diet. Our findings indicate that DGAT1 can utilize a variety of acyl acceptors as substrates in vitro and suggest that these activities may be relevant to the in vivo functions of DGAT1.

Acyltransferases↗
PubMed2001

Use of water-miscible retinyl palmitate as markers of chylomicrons gives earlier peak response of plasma retinyl esters compared with oil-soluble retinyl palmitate.

Delayed peak response of plasma retinyl esters (RE) relative to plasma triacylglycerols (TAG) and apolipoprotein (Apo) B-48 responses following a fat load supplemented with vitamin A raised doubts about the use of vitamin A to label dietary-derived lipids and lipoproteins. The present study compared the use of water-miscible and oil-soluble retinyl palmitate (RP) as markers of dietary-derived lipoproteins in healthy subjects along with the measurements of postprandial plasma TAG and ApoB-48 responses to investigate whether the delayed peak response observed was due to delayed intestinal output of RE from oil-based solutions. Nine healthy female subjects were given a standard test meal containing a dose (112 mg) of RP in either water-miscible or oil-soluble form in random order, on two separate occasions after a 12 h overnight fast. The results showed that the mean plasma RE concentrations reached a peak significantly later than mean plasma TAG and ApoB-48 concentrations when oil-soluble RP was consumed, whereas plasma RE peaked earlier relative to plasma TAG and ApoB-48 responses when water-miscible RP was used. The results suggested a more rapid absorption with a significantly higher and earlier peak response of plasma RE when water-miscible RP was consumed. This was in contrast to the delayed initial appearance and later sustained higher concentrations of plasma RE during the late postprandial period when oil-soluble RP was consumed. The RE response to the water-miscible RP showed better concordance with plasma TAG response than that of oil-soluble RP.

Adult↗
PubMed1987

Factors influencing the level and interanimal variability of retinyl ester hydrolase activity in rat liver.

Retinyl ester hydrolase activity was studied in 25 7-wk-old rats that had been previously fed no vitamin A for 1 wk and then were fed 0, 5, 24, 60 or 240 micrograms retinol/d for 2 wk. This treatment produced rats with vitamin A reserves from depleted to normal (0.03 to 184 micrograms/g) and serum retinol concentrations of 4-67 micrograms/dl. Hydrolase activity in liver homogenates was optimal when assayed with 275 mM CHAPS (3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate), 2 mg/ml Triton X-100 and 5 mM retinyl palmitate at pH 7.0. By use of these concentrations and conditions, retinyl ester hydrolase activity displayed relatively low interanimal variability (fivefold). Furthermore, activity was independent of serum or liver vitamin A concentrations. When CHAPS in the assay was replaced with equimolar sodium cholate, or with reduced concentrations of CHAPS and retinyl palmitate, retinyl ester hydrolase activity was more variable, i.e., 37- and 23-fold, respectively. Furthermore, in the latter case, hydrolase activity was threefold higher in rats with liver vitamin A reserves less than 10 micrograms/g. Thus, the type and concentration of bile salt used to assay retinyl ester hydrolase affect its interanimal variability. Furthermore, hydrolase activity measured in reduced concentrations of substrate and detergent is elevated in rats with low liver reserves of vitamin A.

Animals↗
PubMed1985

Retinyl ester synthesis by the isolated perfused-ventilated neonatal rabbit lung.

Retinyl ester is present in lung but it is unknown if retinyl ester synthesis occurs in that organ. In this study, [3H]-Retinol was perfused into the pulmonary artery of isolated-perfused-ventilated neonatal rabbit lungs. Alumina chromatography was used to separate retinol from retinyl ester in hexane extracts of lung tissue. [3H]-Retinyl ester synthesis did occur and was perfusion time and perfusate [3H]-retinol concentration dependent. Documentation of [3H] retinyl ester synthesis was also made by HPLC analysis of the retinyl ester fraction before and after methanolic KOH hydrolysis. Isolated lung clearly can synthesize retinyl ester.

Animals↗
PubMed1988

Hydrolysis of cis and trans isomers of retinyl palmitate by retinyl ester hydrolase of pig liver.

Relative retinyl ester hydrolase activities of pig liver homogenates (n = 4) toward 9,13-cis-, 13-cis-, 9-cis-, and all-trans-retinyl palmitate were 6.8 +/- 0.5 (SE), 5.7 +/- 0.5, 2.4 +/- 0.1, and 1, respectively. The range of apparent Km values for the four isomers was 142 to 268 microM, and the pH optima were 8-9 in all cases. Peak activities of retinyl ester hydrolase activities in pig liver cytosol toward 13-cis- and all-trans-retinyl palmitate were found in the 20 to 40% and in the 60 to 80% saturated ammonium sulfate (AS) fractions, respectively. By use of size-exclusion chromatography in 2 M KCl, hydrolase activity eluted at volumes corresponding to greater than 2000, 180, and 15 kDa from the 20-40% AS fraction, and at 180 kDa from the 60-80% AS fraction. On the basis of molecular size, different substrate specificities, detergent effects, and susceptibilities to inhibition by phenylmethylsulfonyl fluoride, we conclude that at least three distinct retinyl ester hydrolases are present in pig liver cytosol.

Ammonium Sulfate↗
PubMed1987

Novel aspects of vitamin A metabolism in the dog: distribution of lipoprotein retinyl esters in vitamin A-deprived and cholesterol-fed animals.

Retinyl ester concentrations in plasma from fasting humans, rabbits and rats are usually negligible. In contrast, plasma from fasting dogs contains appreciable amounts of retinyl esters, associated almost entirely with the low-density lipoproteins. This study was undertaken to gather additional information about the nature and origin of canine retinyl ester-containing lipoproteins. We examined the metabolism of endogenous lipoprotein retinyl esters in adult mongrel dogs with moderate vitamin A deficiency. Four animals were fed a diet of oatmeal and tuna fish that provided only 4% of the vitamin A contained in their control rations (15 vs. 367% of the canine recommended daily intake). There was an initial rapid decline in plasma retinyl esters. However, measurable concentrations persisted in plasma for up to 1 year of restricted vitamin A intake. Total plasma retinyl ester concentrations after 6 months of vitamin A deprivation, extrapolated from best-fit monoexponential decay curves for each animal, ranged from 11 to 89% of control, suggesting that there was sustained secretion of retinyl esters from endogenous stores. Density gradient ultracentrifugation of plasma from fasting vitamin A-deprived dogs showed retinyl esters in the very-low- and low-density lipoproteins. After fat and vitamin A feeding retinyl esters appeared among the very-low-, intermediate- and low-density lipoproteins, consistent with the suggestion that chylomicron retinyl esters are first taken up by the liver, and then resecreted as density less than 1.006-1.063 g/ml lipoproteins. Maximal incorporation of dietary retinyl esters into low-density lipoproteins was not reached until 24-48 h. Intermediate-density and beta-migrating low-density lipoprotein retinyl esters were increased markedly in fasting animals maintained on cholesterol- and saturated fat-enriched diets. These observations provide further evidence for the proposal that the canine liver secretes retinyl ester-containing particles, in amounts governed by dietary composition and vitamin A content. What selective advantage this unusual transport pathway might provide is not apparent.

Animals↗
PubMed1994

Epidermis and serum protect retinol but not retinyl esters from sunlight-induced photodegradation.

Sunlight-induced photodegradation of retinyl esters and retinol in human skin, blood and cultured keratinocytes was investigated. Using high-performance liquid chromatography with an extraction method that avoided saponification, the analysis of human foreskin (Caucasian) showed that levels of retinyl esters and retinol were approximately 3.5 and 5.0 times higher, respectively, in the epidermis than in the dermis. Upon irradiation by sunlight, a significant reduction in epidermal retinyl esters was observed in both summer and winter. However, epidermal retinol, dermal retinol and dermal retinyl esters did not show statistically significant reductions. When serum from volunteers who had taken a large dose of retinyl palmitate to elevate serum retinyl esters was exposed to sunlight, the retinyl esters in the serum rapidly disappeared after 10 min of exposure--similar to the photodegradation seen for retinyl palmitate in an organic solvent. While retinol in an organic solvent rapidly photodegraded similar to serum retinyl palmitate, serum retinol slowly declined upon sunlight irradiation. When cultured keratinocytes that took-up 3H-retinol and thereafter contained 3H-retinyl esters and 3H-retinol were exposed to sunlight, 80% of the 3H-retinyl esters disappeared upon sunlight irradiation whereas only about 20% of the 3H-retinol did so. These results suggest that the epidermis, serum and keratinocytes selectively protect retinol from sunlight-induced photodegradation. It is most likely that serum retinol-binding protein and cellular retinol-binding protein protect retinol, a vital epithelial growth factor, from photodegradation.

Blood↗
PubMed1991

Human plasma all-trans-, 13-cis- and 13-cis-4-oxoretinoic acid profiles during subchronic vitamin A supplementation: comparison to retinol and retinyl ester plasma levels.

Plasma concentrations of retinyl esters, retinol, retinol-binding protein and the polar retinol metabolites all-trans-retinoic acid, 13-cis-retinoic acid, all-trans-4-oxoretinoic acid and 13-cis-4-oxoretinoic acid were measured for six male volunteers who received 0.46 mg retinyl palmitate per kilogram body weight as oily drops (equivalent to 0.25 mg retinol per kilogram body weight) once daily over a 20-d period. Retinol and retinol-binding protein levels remained virtually constant throughout the study. Following absorption of vitamin A, retinyl esters as well as all-trans-retinoic acid and 13-cis-retinoic acid were transiently increased in plasma. 13-cis-4-Oxoretinoic acid increased gradually to a steady state level present on d 10 or 20. All-trans-4-oxoretinoic acid was not detected in plasma of the volunteers, with the exception of one on d 10 of the study. Plasma pharmacokinetic profiles of retinyl esters and polar metabolites of retinol displayed great interindividual differences (peak concentrations, time to peak, area-under-the-concentration-time curve values) among the volunteers. Because of the relatively high and consistent steady state concentrations of plasma 13-cis-4-oxoretinoic acid, we suggest that this compound be further investigated as a biochemical marker of vitamin A uptake in humans.

Administration, Oral↗
PubMed1998

Substrate specificity of retinyl ester hydrolase activity in retinal pigment epithelium.

In the eye, hydrolysis of stored retinyl esters is catalyzed by retinyl ester hydrolase (REH) activities in retinal pigment epithelium (RPE) membranes. In the present study, biochemical analyses were conducted to determine the substrate specificity of these activities. Specific activities determined for hydrolysis of various retinol isomers of retinyl palmitate (9-cis-, 11-cis-, 13-cis-, and all-trans-retinyl palmitates) indicated that 11-cis-retinyl palmitate is preferentially hydrolyzed (1.7 nmol/min/mg) compared to the other isomers (0.1-0.3 nmol/min/mg). Examination of the specificity of REH activity for 11-cis-retinyl esters of varied acyl chain length (-myristate, -palmitate, and -stearate) and degree of saturation (-oleate and -linoleate) further demonstrated that palmitate is the preferred fatty acyl moiety. Notably, retinyl esters possessing chain lengths which more closely approximate that of the palmitate ester exhibited higher rates of hydrolysis. Similar results were obtained in retinyl ester-plasma membrane fusion studies in which hydrolysis took place within the membrane domain rather than at the lipid-water interface. REH substrate specificity was further assessed in competition studies in which 11-cis-retinyl palmitate hydrolysis was monitored in the presence of 13-cis-, 9-cis-, or all-trans-retinyl palmitate. Results show that addition of these retinyl palmitate isomers does not affect the rate of hydrolysis of 11-cis-retinyl palmitate. However, the hydrolytic rates associated with other retinyl palmitate isomers were significantly reduced in the presence of 11-cis-retinyl palmitate. Finally, cholesterol ester hydrolase activity was found to be distinct from the observed 11-cis-REH activity and the presence of cholesterol oleate did not affect the rate of 11-cis-retinyl palmitate hydrolysis. Collectively, these data support the hypothesis that a distinct, membrane-associated, 11-cis-retinyl palmitate-specific retinyl ester hydrolase activity exists in the retinal pigment epithelium.

Animals↗