Plasma retinoids after topical use of retinaldehyde on human skin

BACKGROUND: Retinaldehyde (RAL), a natural metabolite of beta-carotene and retinol (ROL), is tolerated by human skin after topical application. PURPOSE: To see if topical application of a large quantity of RAL on human skin is associated with a detectable alteration of constitutive levels of plasma retinoids resulting from metabolism of RAL in the skin. METHODS: Plasma retinoids [ROL, all-trans-retinoic acid (all-trans-RA), RAL, retinyl palmitate/oleate, 13-cis-RA and 4-oxo-13-cis-RA] were analyzed by high-pressure liquid chromatography. Determinations were done in 10 healthy male volunteers kept on a vitamin-A-poor diet before, during and after daily topical application of 7 mg of RAL to 40% of the body surface for 14 days. RESULTS: The introduction of a restricted vitamin A diet before RAL application resulted in a decrease in the plasma levels of ROL, all-trans-RA and retinyl palmitate/oleate. Topical application of RAL did not induce an alteration of the plasma levels of retinoid metabolites. No RAL was detectable in any of the plasma samples. CONCLUSION: The skin metabolism of topically applied RAL does not result in detectable alterations of constitutive levels of plasma retinoids in humans.     

Comparison of the postprandial plasma vitamin A response in young and older adults

To assess the influence of age on vitamin A intestinal and liver metabolism in humans, the postprandial plasma concentrations of intestinal-originated vitamin A, i.e., retinyl esters, and liver-originated vitamin A, i.e., retinol, were compared in eight young (20-30 years old) and eight elderly (64-72 years old) healthy men. Plasma and chylomicron retinyl esters and retinol concentrations were measured for up to 24 h following the intake of a test meal that contained 23,300 RE retinyl palmitate. The chylomicron retinyl palmitate response (area under the curve) was not significantly different between the two groups, but its peak was slightly delayed (1 h) in the elderly men. The proportion of the different retinyl esters secreted in the chylomicrons was not significantly different between the two groups. The postprandial plasma retinol concentration did not change in the young participants, whereas it significantly increased in the elderly. These results suggest that vitamin A intestinal absorption and retinol intestinal esterification processes are not markedly modified in the elderly, whereas the chylomicron clearance and the regulation of postprandial plasma retinol concentration are apparently altered in these subjects.     

Plasma kinetics of vitamin A in humans after a single oral dose of [8,9,19-13C]retinyl palmitate

The kinetics of vitamin A and its major metabolites were investigated in humans. Eleven healthy male subjects ingested 105 mumol (100,000 IU) of [8,9,19-13C]retinyl palmitate in an oily solution. Twenty-seven blood samples were collected during the 1-week study. Plasma samples were analyzed for retinyl esters and for [12C]- and [8,9,19-13C]retinol. Retinol isotopes were quantified using a newly developed GC-MS method. Total retinyl esters peaked at about 4.45 mumol/L from 3.5 to 12 h after dosing. As a result of the perturbation of the tracee system, the plasma concentration of [12C]retinol increased and then decreased as the concentration of [8,9,19-13C]retinol increased, indicating rapid distribution kinetics. A broad single peak (1.16 +/- 0.32 mumol/L) was observed for [8,9,19-13C]retinol at about 10 to 24 h postdose; this likely reflects hepatic secretion of [8,9,19-13C]retinol associated with retinol-binding protein. Then, declining levels of the tracer and increasing levels of the tracee were observed. At its peak, the ingested [8,9,19-13C]retinol reached about 51% of the observed total plasma retinol concentration. This percentage dropped to 13.4% on day 7 indicating slow final elimination from plasma. Our data support the concept that the liver follows the principle "last in/first out' in maintaining vitamin A homeostasis.     

Defects in embryonic hindbrain development and fetal resorption resulting from vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all-trans-retinoic acid

Vitamin A is required for reproduction and normal embryonic development. We have determined that all-trans-retinoic acid (atRA) can support development of the mammalian embryo to parturition in vitamin A-deficient (VAD) rats. At embryonic day (E) 0.5, VAD dams were fed purified diets containing either 12 micrograms of atRA per g of diet (230 micrograms per rat per day) or 250 micrograms of atRA per g of diet (4.5 mg per rat per day) or were fed the purified diet supplemented with a source of retinol (100 units of retinyl palmitate per day). An additional group was fed both 250 micrograms of atRA per g of diet in combination with retinyl palmitate. Embryonic survival to E12.5 was similar for all groups. However, embryonic development in the group fed 12 micrograms of atRA per g of diet was grossly abnormal. The most notable defects were in the region of the hindbrain, which included a loss of posterior cranial nerves (IX, X, XI, and XII) and postotic pharyngeal arches as well as the presence of ectopic otic vesicles and a swollen anterior cardinal vein. All embryonic abnormalities at E12.5 were prevented by feeding pharmacological amounts of atRA (250 micrograms/g diet) or by supplementation with retinyl palmitate. Embryos from VAD dams receiving 12 micrograms of atRA per g of diet were resorbed by E18.5, whereas those in the group fed 250 micrograms of atRA per g of diet survived to parturition but died shortly thereafter. Equivalent results were obtained by using commercial grade atRA or atRA that had been purified to eliminate any potential contamination by neutral retinoids, such as retinol. Thus, 250 micrograms of atRA per g of diet fed to VAD dams (approximately 4.5 mg per rat per day) can prevent the death of embryos at midgestation and prevents the early embryonic abnormalities that arise when VAD dams are fed insufficient amounts of atRA.     

Dietary triglycerides, up to 40 g/meal, do not affect preformed vitamin A bioavailability in humans

OBJECTIVE: Assessing the effect of the dose of dietary triglycerides on preformed vitamin A (retinyl esters) bioavailability in humans. DESIGN: Four test meals containing 15,000 RE retinyl-palmitate and either 0, 15, 30 or 40 g added triglycerides were ingested by eight healthy volunteers, at different days and in a randomized order. SETTING: The study was done in the Hospital Sainte Marguerite, Marseille, France. SUBJECTS: Eight healthy male volunteers were recruited by advertisement. INTERVENTION: Blood samples were collected every hour for seven hours after the test meals intake. Serum and chylomicron (Svedberg flotation unit > 1000) were prepared by centrifugation and retinyl esters were measured by HPLC. RESULTS: The serum retinyl ester response was not significantly lower after the intake of the meal without added triglycerides (7944 +/- 3262 nmol/L h) than after the intake of the fat meals (10012 +/- 2182, 7869 +/- 3157 and 10777 +/- 2067 nmol/L h for the 15, 30 and 40 g-fat meal, respectively), indicating that the serum retinyl ester response was not related to the amount of meal triglycerides. Chylomicron retinyl linoleate response stepwise increased when the amount of meal triglycerides increased while retinyl palmitate and retinyl stearate responses reached a maximum since 15 g triglycerides. Postprandial serum retinol concentration did not change whatever the meal ingested. CONCLUSIONS: (i) a significant amount of preformed vitamin A is apparently absorbed when ingested with trace amount of meal triglycerides only; (ii) meal triglycerides, up to 40 g/meal, do not increase preformed vitamin A bioavailability; (iii) the retinyl ester pattern recovered in the chylomicrons, and probably the esterification process of retinol, is affected by the amount of meal triglycerides; (iv) postprandial retinol homeostasis is not affected by dietary triglycerides.     

Endogenous retinoids in the early avian embryo

Vitamin A is required to rescue the vitamin A-deficient quail embryo from early death, but the endogenous presence of bioactive retinoids has not been documented in these embryos. The analysis of 2000 pooled stage 5-8 normal quail embryos described here provides for the first time direct evidence for the presence of endogenous all-trans-retinoic acid (5 nM) and 3,4-didehydroretinoic acid (4 nM), signaling molecules known to be potent ligands for nuclear retinoic acid receptors. The demonstration of all-trans-retinal (80 nM), all-trans-retinol (100 nM), 3,4-didehydroretinol (200 nM), and retinyl esters (100 nM) suggests the capability of the early avian embryo to generate in situ the vitamin A-bioactive molecules required for development. Analysis of 2100 pooled stage 5-8 quail embryos from vitamin A-deficient eggs revealed no vitamin A-like molecules, supporting the evidence that links vitamin A deficiency in these embryos to abnormalities and early death.     

Long-term administration of high dose vitamin A to rats does not cause fetal malformations: macroscopic, skeletal and physicochemical findings

A rat model was used to investigate whether high oral doses of vitamin A lead to fetal malformations and to what extent retinyl esters (RES) are transferred from the mother to the fetuses. Retinol and RES concentrations in plasma behave similarly in rats and humans. When high concentrations of vitamin A are administered, plasma retinol concentrations remain relatively constant, whereas plasma RES increased in parallel with the dose. To achieve an elevation from approximately 150 to > 1525 nmol x L(-1) in the experimental group before mating, female Ibm: RORO (spf) rats were fed a maintenance diet enriched with 15.2 x 10(3) retinol equivalents (RE) x kg(-1) at the start and increased stepwise to 52.5 x 10(3) for a total of 8 mo. A parallel subgroup was maintained to measure progress in experimental rats without interference by blood taking. Rats of the control group received the basal diet analyzed to contain 4.5 x 10(3) RE x kg(-1). Before mating the mean body weights of experimental and control rats were not significantly different. All-trans, 13-cis, 4-oxo-all-trans and 5,6-epoxy-all-trans retinoic acid (RA) concentrations were determined in maternal and fetal plasma. With high vitamin A intake, 4-oxo- and 5,6-epoxy RA concentrations were significantly higher in the fetuses than in their mothers. Although these high intakes of vitamin A by the rat dams resulted in high maternal and fetal plasma concentrations of vitamin A and its metabolites, fetal malformations were not observed. This may be due to the fact that circulating RES are not teratogenic and that after crossing the placental barrier, they are stored mainly in fetal liver.     

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the lymphatic absorption of a single oral dose of [3H]retinol and on the intestinal retinol esterification in the rat

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the turnover of vitamin A in the body and inhibits the normal hepatic accumulation of dietary vitamin A. Vitamin A is absorbed in the small intestine, where it is incorporated into chylomicrons as retinyl esters for release into the lymph and further distributed via blood to the liver for storage. The aim of the present study was to investigate if the decreased hepatic vitamin A levels in TCDD-exposed rats could be due to impaired intestinal absorption of vitamin A via lymph. Male Sprague-Dawley rats were given a single oral dose of TCDD (10 microg/kg). Five days after administration, the main intestinal lymph duct of the rats was cannulated. After a 24-h recovery from surgery, the rats were each given a single dose of [3H]retinol in corn oil via gavage and the lymph was collected for 24 h. The cumulative radiolabel recovered in the intestinal lymph was significantly lower in TCDD-treated than in control rats during the first 6 h of absorption. However, no significant differences in radiolabel recovered in lymph were seen when looking at the entire 24-h collection period. In the intestinal mucosa, retinol esterification catalyzed by the enzyme lecithin:retinol acyl transferase (LRAT) or acyl coenzyme A (CoA):retinol transferase (ARAT) was not statistically different between the groups. However, mucosal retinyl palmitate levels were significantly increased in TCDD-treated rats. In conclusion, a small and transient reduction was found of the uptake of vitamin A into the lymph of TCDD-treated rats. It is obvious that this finding cannot explain the TCDD-induced decrease in hepatic vitamin A levels in the rat. Rather, a combination of inhibited retinol esterification in hepatic stellate cells, increased release of endogenous vitamin A, and increased hepatic catabolism of retinoids could explain the effect of TCDD on liver retinoid levels.     

Effect of vitamin A deficiency on the early response to experimental Pseudomonas keratitis

PURPOSE: Vitamin A-deficient humans and animals are more susceptible to infections than are healthy humans and animals. This study compares the early corneal response (within 24 hours) to an experimental Pseudomonas aeruginosa infection between vitamin A deficient and control rats. METHODS: Male WAG/Rij/MCW rats were fed either a vitamin A- deficient diet (A-) or the same diet with retinyl palmitate added back in a nonrestricted manner (N) or under pair-fed conditions (A+) to yield weight-matched rats. Some A-rats were repleted wih retinyl palmitate 16 days before being killed and then given free access to the retinyl palmitate-supplemented diet (R). Twenty-four hours before being killed, the corneas of anesthetized rats were scratched and P. aeruginosa organisms were applied to the corneal surface. The rats were killed using an overdose of sodium pentobarbital. Corneas were either processed for light and electron microscopic examination or extracted for proteinase and myeloperoxidase determination. Corneal myeloperoxidase concentrations relative to neutrophil myeloperoxidase concentrations were used to determine the number of neutrophils in the cornea. Zymography was used to study caseinases, gelatinases, and plasminogen activators. Reverse zymography was used to detect proteinase inhibitors. Similar results were noted at early, mid, and late weight plateau stages of vitamin A deficiency. RESULTS: Ulceration occurred within 24 hours when low numbers of P. aeruginosa (10(4) cpu) were applied topically onto scratched A- corneas, whereas no ulceration was observed in the A+, R, and N corneas. When higher numbers of P. aeruginosa (10(7)-10(8)) were applied to the scratched corneas, all corneas became ulcerated within 24 hours. The extent of ulceration in the control corneas was greater than that in A- corneas by a factor of two. Only the A- corneas contained inflammatory cells with unusual striated deposits in phagolysosomes. The total number of neutrophils in the cornea and the concentrations of caseinases, plasminogen activators, and gelatinases in the infected corneal extracts were similar; however, the concentrations of cysteine proteinase inhibitors were elevated under A- conditions. CONCLUSIONS: Vitamin A deficiency alters the response of the cornea to a P. aeruginosa infection during the first 24 hours. The alterations observed are probably due to multiple factors: an insufficient tear film for bacterial clearance and migration of neutrophils, epithelial keratinization, alterations in corneal wound healing, and changes in polymorphonuclear function.     

Plant sources of vitamin A and human nutrition: red palm oil does the job

Studies in India demonstrate that the beta-carotene in red palm oil is as effective as high-dose retinyl palmitate as a supplement to restore and preserve vitamin A nutriture in schoolchildren and may be an effective food-based strategy to combat hypovitaminosis A.     

A place for palm fruit oil to eliminate vitamin A deficiency

There is general consensus that food-based approaches are viable and sustainable options for addressing vitamin A deficiency in populations. One such example is the fortification of food which, if properly monitored, could make a significant contribution towards improving the vitamin A status of populations throughout the world. Red palm fruit oil (RPO) with its high content of natural carotenoids, lends itself exceptionally well to this purpose at both household and commercial level. Results are now available from several feeding trials incorporating RPO into diets at household level or into commercially manufactured products. RPO in the maternal diet was shown to improve the vitamin A status of lactating mothers and their infants. Consumption of RPO incorporated in a sweet snack or biscuits significantly improved plasma retinol concentrations in children with subclinical vitamin A deficiency. There is evidence that if only 35-50% of the recommended daily intake for vitamin A were to be provided by RPO, it may be sufficient to prevent vitamin A deficiency (hypovitaminosis A). Red palm oil has a highly bioconvertible form of alpha- and beta-carotene, a long shelf life, and a higher cost/benefit ratio when compared to other approaches such as high-dose-vitamin A supplements and fortification of foods with retinyl ester fortificants. Consumption of RPO is safe and cannot produce hypervitaminosis A. Considering all the current information about RPO, the initiation of food-based interventions involving its use in developing countries with an endemic vitamin A deficiency problem, appears to be a logical choice.     

Clearance of chylomicron remnants in normolipidaemic patients with coronary artery disease: case control study over three years

OBJECTIVE: To test the hypothesis that subjects who clear chylomicron remnants slowly from plasma may be at higher risk of coronary artery disease than indicated by their fasting plasma lipid concentrations. DESIGN: Case control study over three years. SETTING: An 800 bed general municipal hospital. SUBJECTS: 85 normolipidaemic patients with coronary artery disease selected prospectively and matched with 85 normolipidaemic subjects with normal coronary arteries on angiography. INTERVENTIONS: All subjects were given a vitamin A fat loading test which specifically labels intestinal lipoproteins with retinyl palmitate. MAIN OUTCOME MEASURE: Postprandial lipoprotein metabolism. RESULTS: The area below the chylomicron remnant retinyl palmitate curve was significantly increased in the coronary artery disease group as compared with the controls (mean 23.4 (SD 15.0) v 15.3 (8.9) mumol/l.h; 95% confidence interval of difference 4.37 to 11.82). CONCLUSION: Normolipidaemic patients with coronary artery disease had significantly higher concentrations of chylomicron remnants in plasma than normolipidaemic subjects with normal coronary vessels. This may explain the mechanism underlying the susceptibility to atherosclerosis of coronary artery disease patients with normal fasting lipid values. As diet and drugs can ameliorate the accumulation of postprandial lipoproteins in plasma, the concentration of chylomicron remnants should be measured in patients at high risk of coronary artery disease.     

Reduced lecithin:retinol acyl transferase activity in cultured squamous cell carcinoma lines results in increased substrate-driven retinoic acid synthesis

The uptake and metabolism of retinol was compared in squamous cell carcinoma lines, SCC12b and SCC13, and in normal human keratinocytes (NHK). Long chain fatty acid esters of retinol and 3,4-didehydroretinol were the predominant metabolites formed in both cell types. Lesser amounts of unesterified retinol, 3,4-didehydroretinol, and their respective active acid forms were also observed. Despite a qualitatively similar retinoid composition, there were significant quantitative differences between cell types. Most notable was that SCC formed only about one-fourth the retinoid ester as did normal cells. In parallel with this, unesterified retinol and retinoic acid concentrations in SCC were significantly elevated over those in normal cells. This altered pattern of retinoid metabolites in SCC was found to be due to very low lecithin:retinol acyltransferase (LRAT) activity. SCC exhibited less than one-tenth the LRAT activity of normal cells. Acyl-coenzyme A:retinol acyltransferase (ARAT) and retinyl ester hydrolase activities were not different between cell types. Challenging cells with increasing medium retinol concentrations resulted in dose-dependent increases in retinol and retinoic acid within SCC. In contrast, retinol and retinoic acid concentrations in similarly challenged normal cells remained relatively low across a wide retinol concentration range. This was accomplished by the storage of retinol, via LRAT activity, as retinyl ester. Consistent with increased substrate-driven retinoic acid synthesis in SCC, the expression of transglutaminase 1 was suppressed to a greater extent in the SCCs than in NHK, when cells were exposed to equivalent medium concentrations of retinol. The data demonstrate a central role of LRAT in regulating retinoic acid synthesis via its capacity to modulate cellular levels of substrate retinol.     

Storage of vitamin A in extrahepatic stellate cells in normal rats

In mammals, vitamin A is primarily stored as retinyl esters in hepatic stellate cells under normal dietary intake of the vitamin. Previously, extrahepatic vitamin A-storing stellate cells have only been identified in animals maintained on a vitamin A-rich diet, and it has not been known whether these cells play a role in normal vitamin A metabolism. The purpose of this study was, to quantify the stellate cell lipid droplet area in hepatic and extrahepatic stellate cells in control rats and in rats fed excess vitamin A. The stellate cells were identified by the gold chloride staining technique, specific autofluorescence of retinyl ester, and by electron microscopy. The stellate cell lipid droplet area was then quantitated by the use of morphometric quantitation. We demonstrated that lipid droplet-containing stellate cells were identified in liver, lung, kidney, and intestine, in normal as well as vitamin A-fed rats. The area of lipid droplets in liver, lung, and intestine stellate cells of normal rats was 0.2, 0.3, and 0.04 mm2 per cm2 tissue, respectively. When the rats were administered excess vitamin A, the hepatic, lung, and intestinal stellate cell lipid droplet area increased about 10-fold, 2-fold, and 40-fold, respectively. Thus the present study shows that extrahepatic stellate cells in lung and intestine of normal rats contain lipid droplets, and that these lipid droplets increase in area when high doses of vitamin A are fed to the animals. These data suggest that not only liver stellate cells but also extrahepatic stellate cells play an important role in vitamin A storage in normal as well as vitamin A-fed animals.     

Evidence that vitamin A is not required for the biosynthesis of ovalbumin in chicks

Four-day-old pullets fed a vitamin A-deficient diet were stimulated daily with 1 mg 17beta-estradiol-3-benzoate/day for 6 to 19 days. The onset of vitamin A deficiency had no effect on oviduct growth in these chicks; even though vitamin A-deficient chicks showed a severe decline in growth rate while controls (fed the same diet supplemented with retinyl palmitate) continued to grow, estrogen stimulated resulted in similar oviduct size. Ovalbumin concentrations of estrogen-stimulated chicks were determined by immunoprecipitation of the soluble protein supernatant fraction of oviduct. The concentration of ovalbumin in oviducts of chicks fed a vitamin A-supplemented diet was similar in the concentration in oviducts of chicks fed a vitamin A-deficient diet. The incorporation of [3H]glucosamine and 14C-amino acids into immunoprecipitable ovalbumin, following the in vitro incubation of minced oviduct, indicated that ovalbumin synthesis was not affected by vitamin A deficiency. The specific activity of incorporated [3H]glucosamine, the 14C-amino acid incorporation into ovalbumin, the relative rate of ovalbumin synthesis, and the relative effiency of [3H]glucosamine incorporation into ovalbumin were each similar between the two diet groups. The relative efficiency of [3H]glucosamine incorporation into sodium dodecyl sulfate and dithiothreitol extractable membranous proteins of oviduct was not affect by vitamin A deficiency.     

Variability in the oral bioavailability of all-trans-retinoic acid

BACKGROUND: Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies. PURPOSE: This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy. METHODS: Six patients with solid tumors received oral doses of 10-mg gelatin capsules of all-trans-RA. Patients were studied on 2 consecutive days after they received 28 days of all-trans-RA administered as two daily 78-mg/m2 doses. The study assigned the patients to two groups. Three patients took a 156-mg/m2 dose on day 28 and a 78-mg/m2 dose on day 29; the other three patients took the lower dose on day 28 and the double dose on day 29. Blood samples for the determination of all-trans-RA plasma concentration were obtained at 30-minute intervals starting just prior to drug administration and continuing for a total of 7 hours. The plasma concentration of all-trans-RA was measured by high-performance liquid chromatography. RESULTS: Plasma concentrations following an oral dose of all-trans-RA were highly variable, with peak concentrations ranging from 0.07 to 1.2 microM for the 78-mg/m2 dose level. Doubling the dose from 78 to 156 mg/m2 increased plasma concentration in all six patients, but the increase was unpredictable and not related to dose, ranging from less than a 1.2-fold to more than a 10-fold increase. CONCLUSION: The current study does not support the hypothesis that the gastrointestinal absorption of all-trans-RA involves a saturable process but instead suggests that absorption is highly variable among patients. This wide interpatient variability suggests that pharmacokinetic drug monitoring may have an important role in the management of patients receiving all-trans-RA.     

Effects of dietary vitamin D intake on plasma levels of parathyroid hormone and vitamin D metabolites in healthy Japanese

To clarify the nutritional status of vitamin D in Japanese, effects of dietary intake of vitamin D on plasma levels of intact and highly sensitive parathyroid hormone (I-PTH and HS-PTH), 25-hydroxyvitamin D (25-OH-D), 1,25-dihydroxyvitamin D (1,25(OH)2D), calcium (Ca) and phosphorus (P(i)) in 79 healthy Japanese were investigated. The plasma levels of 25-OH-D in men were significantly higher than those in women, whereas those of HS-PTH in men were significantly lower than those in women. The levels of 25-OH-D in men were generally higher than those in women. Significant correlations were observed between the dietary vitamin D intake and the plasma 25-OH-D or HS-PTH levels. Correlations between the plasma 25-OH-D levels and the plasma HS-PTH levels were also significant. These results suggest that dietary intake of sufficient amounts of vitamin D is effective for improving the vitamin D nutritional status through normalizing PTH levels.     

Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.     

Anhydroretinol, a retinoid active in preventing mammary cancer induced in rats by N-methyl-N-nitrosourea

As determined by in vitro tests, anhydroretinol, a metabolic product of retinol, was bound specifically by serum retinol-binding protein and by cellular retinol-binding protein but not by cellular retinoic acid-binding protein or the nuclear receptors, RARs and RXRs. For rats dosed with the mammary carcinogen, N-methyl-N-nitrosourea (45 mg/kg body weight) and given diets containing either the retinoid vehicle, anhydroretinol (67, 134, 268, or 536 mg/kg of diet), or retinyl acetate (328 mg/kg of diet), there were, over a 90-day observation period, no significant differences in body weights. The compound did not accumulate in liver tissue or cause an increase in hepatic levels of retinyl palmitate (potential problems observed with other retinoids). The numbers of mammary cancers were as follows: no retinoid, 4.5/rat; retinyl acetate, 2.1/rat; and increasing doses of anhydroretinol, 2.9, 3.3, 3.0, and 1.7/rat, respectively. Thus, anhydroretinol, at non-toxic levels, was effective as a preventive agent in this experimental model of breast cancer.     

Effects of vitamins A and E on the antioxidative metabolism of weaning pigs given dietary fats of different qualities

Early weaned piglets were divided into eight groups of 6 animals each. The animals were fed diets differing in fat quality (4% soybean oil, POZ 5 or 176) and in the content of the vitamins A (5,000 or 20,000 I.U./kg) and E (25 or 125 I.U./kg) over a period of 7 weeks. At the beginning, on day 25 and 47 blood samples were taken and analysed for vitamin A and E. In liver, heart, M. longissimus dorsi and M. semitendinosus vitamin A, E and the TBA-reactive substances were analysed. Induced lipid peroxidation was assessed by the ethane and pentane production rate in the skeletal muscle. During the weaning period a decrease in the alpha-tocopherol level was observed. In groups with the lower doses of vitamin E this effect was more pronounced. After 47 days the alpha-tocopherol concentrations in plasma and heart and skeletal muscle fell about 25-30% by offering high doses of vitamin A compared to those groups fed low doses. Oxidized fats also led to lower tocopherol concentrations in muscle tissues. Hydrocarbon production in M. longissimus dorsi and M. semitendinosus was significantly reduced in groups with the high supplement of vitamin E. A tendentially opposite effect was seen in groups supplied with high levels of vitamin A or oxidized fat. Although retinyl esters in plasma are a minor fraction of the vitamin A activity, they present 99% of the vitamin A in the liver. The distribution pattern of the different retinyl esters was independent of the amount of supplementary vitamin A. In the present experiment 20,000 U of Vitamin A reduced plasma and tissue vitamin E levels. This effect led to an increase of lipid peroxidation indicated by the higher production of hydrocarbons. The results raise concerns about further increases of vitamin A supplementation in piglet feed.