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Biomedical subjects

N I Krinsky

Publications and source records attributed to N I Krinsky.

At least 37 records · Page 2Linked to original sources
PubMed1996

Beta-oxidation in rabbit liver in vitro and in the perfused ferret liver contributes to retinoic acid biosynthesis from beta-apocarotenoic acids.

The biosynthesis of retinoic acid from beta-apocarotenoic acids was examined for a beta-oxidation-like process using both rabbit liver mitochondrial fractions with various beta-apocarotenoic acids (beta-apo-14'-, beta-apo-12'-, and beta-apo-8'-carotenoic acid) and perfusion in ferret liver through the portal vein with beta-apo-8'-carotenoic acid. The in vitro incubation of beta-apo-8', beta-apo-12'-, and beta-apo-14'-carotenoic acids gave rise to shorter chain beta-apocarotenoic acids as well as retinoic acid. The rate of retinoic acid synthesis from 10 microM beta-apo-8', beta-apo-12'-, and beta-apo-14'-carotenoic acids was 11 +/- 2, 18 +/- 3, and 30 +/- 7 pmol/h/mg of protein, respectively. The stepwise oxidation of beta-apocarotenoic acid in mitochondria was dose-related to both protein concentration and substrate concentration. beta-Apocarotenoic acid oxidation was inhibited in a dose-dependent manner when it was co-incubated with oleoyl-CoA. The in vivo perfusion of ferret liver with beta-apo-8'-carotenoic acid resulted in a linear increase in the retinoic acid concentration of bile, which was completely abolished by co-perfusion of 3-mercaptopropionic acid, an inhibitor of long chain acyl-CoA dehydrogenase, and partially inhibited by 2-tetradecylglycidic acid, an inhibitor of carnitine-palmitoyl-CoA transferase I. However, the formation of retinoic acid from the beta-apocarotenoic acids was not inhibited, either in vitro or in vivo, by citral, an inhibitor of retinal oxidase. Thus, the formation of retinoic acid was not occurring by the central cleavage pathway. These data suggest that the oxidation of intermediate compounds between beta-carotene and retinoic acid may undergo a type of beta-oxidative process to form retinoic acid, which is reminiscent of mitochondrial fatty acid beta-oxidation. This pathway may play an important role in the biosynthesis of retinoic acid from beta-carotene.

Animals↗
PubMed1996

Sex differences in macular pigment optical density: relation to plasma carotenoid concentrations and dietary patterns.

Sex differences in macular pigment (MP) optical density (measured psychophysically) were examined. Concentrations of lutein and zeaxanthin (L and Z) (non-separated) and beta-carotene (BC) in the blood were determined using reverse phase high-performance liquid chromatography. Dietary intake of L and Z, BC, fat, and iron were estimated by questionnaire. Males had 38% higher MP density than females (P < 0.001) despite similar plasma carotenoid concentrations and similar dietary intake (except for fat). Dietary intake of carotenoids, fat and iron, as well as plasma concentrations of L and Z were positively related to MP density in males. Conversely, only plasma L and Z was related to MP density for females, and dietary fat was negatively related to MP density. Sex differences in protection of the retina by MP and in the relationship between the retina, blood and diet could be a factor in the incidence of retinal diseases, especially age-related macular degeneration.

Adult↗
PubMed1996

Serum response of all-trans and 9-cis isomers of beta-carotene in humans.

OBJECTIVE: Little work has been performed on the serum response of various carotene isomers. The present study was carried out to examine the serum response of all-trans and 9-cis isomers of beta-carotene (BC) using frequent blood sample collections at early time points. METHODS: Serum responses of all-trans BC and a mixture of BC isomers containing 80% 9-cis BC were studied in 15 men by measuring the serum concentrations of BC at 1, 3, 5, 7, 9, 12, and 24 hours after a single large oral dose of all-trans BC or 9-cis BC. RESULTS: The serum response to an oral dose of all-trans BC (120 mg) significantly increased from baseline at 24 hr (p < 0.004). After an oral dose of a mixture of BC isomers (120 mg, 80% 9-cis BC), the peak concentration of 9-cis BC was significantly greater that baseline values (p < 0.016). CONCLUSIONS: Increases in serum all-trans BC levels, in part, may be due to greater intestinal absorption, whereas the inability to measure a significant increase in the concentration of 9-cis BC may indicate poor absorption, isomerization to all-trans BC, or a very rapid tissue uptake.

Adult↗
PubMed1996

Human plasma carotenoid response to the ingestion of controlled diets high in fruits and vegetables.

Plasma carotenoid responses were determined in 36 healthy men and women before and after being fed controlled diets with a moderate amount of fat (26% of total energy) and a high carotenoid content (approximately 16 mg/d) for two 15-d periods. In addition, broccoli (205 g/d) was provided either during the first or the second 15-d residency period in a crossover design. Plasma was digested with lipase and cholesterol esterase, and carotenoids were extracted and measured by using HPLC. Three oxygenated carotenoids (lutein, zeaxanthin, and cryptoxanthin), three hydro-carbon carotenoids (alpha-carotene, all-trans-beta-carotene, and 13-cis-beta-carotene), and four geometric isomers of lycopene (15-cis-, 13-cis-, 9-cis-, and all-trans-lycopene) were separated by using a C30 carotenoid column. A small unidentified peak coeluted with standard 9-cis-beta-carotene and was identified as zeta-carotene (lambda(max) = 400 nm). The concentrations of plasma lutein, cryptoxanthin, alpha-carotene, 13-cis-beta-carotene, all-trans-beta-carotene, and cis- and trans-lycopenes were all significantly increased (P < 0.05) on days 6-16 by the high-fruit and -vegetable diets. The provision of additional broccoli for 5 d to the basic high-carotenoid diet resulted in a further significant increase in the serum concentration of lutein compared with the feeding of the basic high-carotenoid diet alone. Most of the measurable carotenoids of human plasma can be increased by moderate alterations in diet within a short time, although the magnitude of the plasma response may be related to the baseline carotenoid concentrations.

Adult↗
PubMed1995

Similar metabolites formed from beta-carotene by human gastric mucosal homogenates, lipoxygenase, or linoleic acid hydroperoxide.

To determine the basis for the formation of excentric cleavage products of beta-carotene (beta-C) after incubation with human gastric mucosal homogenates, we have studied the effect of lipoxygenase in beta-C metabolism. beta-C was incubated with human gastric mucosal homogenates, soybean lipoxygenase with linoleic acid, or the lipoxygenase primary product, 13(S)-hydroperoxycis,trans-9,11-octadecadienoic acid (13-LOOH). The beta-C metabolites, beta-apo-14', -12', -10', and -8'-carotenals, beta-apo-13-carotenone, retinoic acid, and retinal were detected and quantified by HPLC after a 30-min incubation with 1.8 microM beta-C. The products from the lipoxygenase plus linoleic acid incubation and from the lipoxygenase primary product, 13-LOOH, with beta-C were exactly the same as the products from a human gastric mucosal homogenate incubation. Significantly larger amounts of the same beta-C metabolites were formed when beta-C was incubated with gastric mucosal homogenates and lipoxygenase together. Furthermore, nordihydroguaiaretic acid (NDGA), a specific lipoxygenase inhibitor, was found to significantly inhibit the formation of beta-apo-carotenoids and retinoids produced by gastric mucosal homogenates incubated with beta-C. The similarity of the beta-C metabolites when beta-C was incubated with human gastric mucosal homogenate, lipoxygenase plus linoleic acid, or 13-LOOH and the inhibition of beta-C metabolite production by NDGA in gastric tissue incubation with beta-C suggest that lipoxygenase is involved in beta-C metabolism in gastric mucosa. The activity of 13-LOOH in our hands would indicate that an enzyme-linked process is occurring in gastric tissue producing fatty acid hydroperoxides, and that the hydroperoxide, or a radical species derived from it, is able to carry out the oxidation of beta-C independently of the enzyme.

Biotransformation↗
PubMed1995

Supplementation with beta-carotene in vivo and in vitro does not inhibit low density lipoprotein oxidation.

The inhibition of low density lipoprotein (LDL) oxidation has been postulated as one mechanism by which antioxidants may prevent the development of atherosclerosis. Available data on the ability of beta-carotene to inhibit LDL oxidation are conflicting. We examined the role of in vivo and in vitro supplementation with beta-carotene on metal ion-dependent (cupric ions, Cu2+) and metal ion-independent (2,2'-azobis[2-amidinopropane]dihydrochloride, AAPH) oxidation of LDL as measured by the formation of conjugated dienes (absorbance at 234 nm). Sixteen subjects were supplemented with 50-100 mg of beta-carotene on alternate days for 3 weeks following a week-long loading dose of 100 mg/day. Plasma beta-carotene levels rose 5.5-fold, while LDL beta-carotene levels rose 8.5-fold. Oxidation of LDL by Cu2+ or AAPH was not significantly delayed after in vivo supplementation with beta-carotene compared with baseline. For AAPH, the lag phase (in minutes) was 75 +/- 8 at baseline and 83 +/- 14 after supplementation (P = 0.07). For Cu2+, the lag phase was 172 +/- 41 at baseline and decreased to 130 +/- 24 after supplementation (P < 0.01). Similarly, no protective effect against Cu(2+)-induced oxidation was observed when beta-carotene was added to LDL in vitro. Supplementation of plasma with beta-carotene in vitro prior to LDL isolation also did not enhance LDL's resistance to Cu(2+)- or AAPH-induced oxidation, despite a 5-fold increase in LDL beta-carotene levels over vehicle control.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Vitamin E enhances the lymphatic transport of beta-carotene and its conversion to vitamin A in the ferret.

BACKGROUND/AIMS: beta-Carotene and alpha-tocopherol may have either antagonistic or synergistic effects on each other's absorption and metabolism. The effects of both physiological and pharmacological concentrations of alpha-tocopherol on the absorption and metabolism of beta-carotene in ferret intestine were determined. METHODS: A high concentration of beta-carotene was perfused through the upper portion of the small intestine of ferrets in vivo with varying levels of alpha-tocopherol. The effluent of a mesenteric lymph duct cannulation, the intestinal mucosal scraping, and portal vein blood were sampled and analyzed by high-performance liquid chromatography. RESULTS: The lymphatic transport of beta-carotene was enhanced 4-fold by alpha-tocopherol at a physiological dose and 12-21-fold at a pharmacological dose. The lymphatic transport of alpha-tocopherol was linearly (r = 0.8; P < 0.05) related to the luminal alpha-tocopherol concentration even in the presence of a high concentration of beta-carotene. Furthermore, alpha-tocopherol increased the conversion of beta-carotene into retinol in the intestine in a dose-dependent manner. CONCLUSIONS: alpha-Tocopherol has a positive effect on the intestinal absorption of intact beta-carotene and may modulate the metabolic conversion of beta-carotene into retinoids.

Absorption↗
PubMed1995

Plant carotenoids and related molecules: important dietary antioxidants.

The antioxidant effects of dietary carotenoids such as beta-carotene have been well documented in various systems in vitro, using either organic solvents or membrane systems. However, the biologically relevant studies of the effects of beta-carotene on low-density lipoprotein (LDL) oxidation are still controversial, as are those studies using LDL from individuals supplemented with large amounts of beta-carotene. These findings do not agree with the epidemiological evidence which suggests that individuals who consume fruits and vegetables rich in carotenoids, or who have relatively high serum carotenoid levels, are at a lower risk of developing coronary heart disease. What is apparent is that studies that have looked at antioxidant protection in the whole organism have demonstrated a decrease in markers of lipid peroxidation after beta-carotene supplementation. Maybe those studies trying to pin-point the antioxidant site of carotenoids in vivo have been looking at the wrong tissue.

Antioxidants↗
PubMed1995

Discrimination in absorption or transport of beta-carotene isomers after oral supplementation with either all-trans- or 9-cis-beta-carotene.

Human subjects (n = 24) were supplemented with 100 mg beta-carotene/d for 6 d, either as synthetic all-trans-beta-carotene or a natural beta-carotene preparation derived from the alga Dunaliella salina, which consists of a 50:50 mixture of all-trans- and 6-cis-beta-carotene. This loading dose was followed by a 23-d maintenance dose consisting of alternate-day supplementation with 50 mg all-trans-beta-carotene or either 66 or 100 mg of the natural 50:50 isomeric mixture. The loading dose resulted in significant increases in plasma concentrations of both isomers, with the all-trans-beta-carotene-supplemented group showing a 7.2- and 5.0-fold increase in the all-trans and 9-cis concentrations in plasma, respectively. The group receiving the 50:50 mixture showed a 4.0- and 3.7-fold increase in the all-trans and 9-cis concentrations in plasma, respectively, without any apparent dose-dependency. However, even with the 50:50 mixture, the 9-cis concentrations were only a small fraction of the total plasma beta-carotene. Results after an additional 23-d period of alternate-day supplementation were not significantly different from those described above for the 6-d supplementation. Increases in low-density-lipoprotein concentrations of total beta-carotene correlated strongly with the increases seen in plasma concentrations. Lipid-soluble antioxidants vitamin E and ubiquinol were unaffected by beta-carotene supplementation. However, the amount of lycopene in the low-density lipoprotein decreased during this supplementation period. A strong discrimination between these two geometric isomers of beta-carotene was demonstrated, although the tissue site of discrimination was not determined.

Administration, Oral↗
PubMed1995

Intestinal absorption and metabolism of 9-cis-beta-carotene in vivo: biosynthesis of 9-cis-retinoic acid.

This study was done to examine the intestinal absorption and cleavage of 9-cis-beta-carotene in vivo. A micellar solution, containing either no addition or 10 mumol of 9-cis- or all-trans-beta-carotene, was perfused for 2 h through the upper portion of the small intestine of ferrets. The effluent of a mesenteric lymph duct cannulation was collected, as well as intestinal mucosa scrapings, a portal blood sample, and a liver biopsy, both before and after perfusion. Carotenoids and retinoids were measured by reverse-phase, high performance liquid chromatography. 9-Cis- and all-trans-beta-carotene were transported equally well into mesenteric lymph, although the intestinal concentration of the corresponding isomer was tenfold higher after perfusion of the 9-cis- isomer than after perfusion of all-trans-beta-carotene. Regardless of which isomer was used, perfusion of beta-carotene resulted in the biosynthesis of similar amounts of retinoic acid in portal blood, liver, and intestine. However, after the perfusion of all-trans-beta-carotene, all the retinoic acid formed was in the all-trans- form, whereas the perfusion of 9-cis-beta-carotene resulted in the biosynthesis of about 50% of the total retinoic acid as the 9-cis-isomer. We conclude that in the in vivo ferret model, 9-cis-beta-carotene has a good bioavailability and is a precursor of 9-cis-retinoic acid.

Animals↗
PubMed1994

Biosynthesis of 9-cis-retinoic acid from 9-cis-beta-carotene in human intestinal mucosa in vitro.

The role of 9-cis-beta-carotene (9-cis-beta-C) as a potential precursor of 9-cis-retinoic acid (9-cis-RA) has been examined in human intestinal mucosa in vitro. By using HPLC, uv spectra, and chemical derivatization analysis, both 9-cis-RA and all-trans-retinoic acid (all-trans-RA) have been identified in the postnuclear fraction of human intestinal mucosa after incubation with 9-cis-beta-C at 37 degrees C. The biosynthesis of both 9-cis-RA and all-trans-RA from 9-cis-beta-C was linear with increasing concentrations of 9-cis-beta-C (2-30 microM) and was linear with respect to tissue protein concentration up to 0.75 mg/ml. Retinoic acid was not detected when a boiled incubation mixture was incubated in the presence of 9-cis-beta-C. The rate of synthesis of 9-cis- and all-trans-RA from 4 microM 9-cis-beta-C were 16 +/- 1 and 18 +/- 2 pmol/hr/mg of protein, respectively. However, when 2 microM all-trans-beta-C was added to the 4 microM 9-cis-beta-C, the rate of all-trans-RA synthesis was increased to 38 +/- 6 pmol/hr/mg of protein, whereas the rate of 9-cis-RA synthesis remained the same. These results suggest that 9-cis-RA is produced directly from 9-cis-beta-C. Furthermore, incubations of either 0.1 microM 9-cis- or all-trans-retinal under the same incubation conditions showed that 9-cis-RA could also arise through oxidative conversion of 9-cis-retinal. Although only 9-cis-RA was detected when 9-cis-RA was used as the substrate, the isomerization of the all-trans-RA to 9-cis-RA cannot be ruled out, since both all-trans-RA and trace amounts of 9-cis-RA were detected when all-trans-retinal was incubated as the substrate. These data indicate that 9-cis-beta-C can be a source of 9-cis-RA in the human. This conversion may have a significance in the anticarcinogenic action of beta-C.

Carotenoids↗
PubMed1994

Effects of retinoids, beta-carotene, and canthaxanthin on UV- and X-ray-induced transformation of C3H10T1/2 cells in vitro.

We observed that various retinoids (including all-trans-retinoic acid, 13-cis-retinoic acid, and the synthetic retinoid Ro-11-1430) have approximately the same ability to suppress ultraviolet light-induced transformation of C3H10T1/2 cells in vitro. Retinoids also suppress X-ray induced transformation in vitro. Ro-11-1430 has no effect when present for only 1 day after the X-ray exposure but does have a suppressive effect on radiation transformation when present for 5 or 10 days after irradiation. Ro-11-1430 has its major suppressive effect on X-ray transformation when present in irradiated cultures in the confluent stationary phase of growth. Natural beta-carotene (type IV) from carrots, but not synthetic beta-carotene, has the ability to suppress radiation (X-ray)-induced transformation when present for the entire transformation assay period. Natural beta-carotene is without effect on the transformation process when present in irradiated cultures only during confluence. For these retinoids, as well as beta-carotene and canthaxanthin, there is a highly significant suppressive effect on radiation transformation and radiation transformation enhanced by 12-O-tetradecanoylphorbol-13-acetate when the compounds are present at toxic levels; when nontoxic levels are utilized, these compounds have the ability to suppress the yield of transformed cells to approximately one-half of that observed in irradiated cultures in the absence of these compounds. A selective toxicity for transformed cells appeared to exist for the beta-carotene-treated F-17 cells. This apparent selective toxicity was not observed in another line of transformed cells. Cl 16 cells, or in human cells. We observed different uptake patterns of beta-carotene by nontransformed C3H10T1/2 cells, F-17 cells, and Cl 16 cells that may account for the observed apparent selective toxicity of one line of transformed cells (F-17 cells) to beta-carotene.

Animals↗
PubMed1993

Micronutrients and their influence on mutagenicity and malignant transformation.

Many studies have now indicated that micronutrients, such as the carotenoids, tocopherols, and ascorbic acid, can prevent mutagenesis, genotoxic effects, or malignant transformation in bacteria and mammalian tissue, either in cell culture or in organ culture. In addition, multiple papers report that some of these micronutrients act as anticarcinogenic agents in animals treated with either ultraviolet light, ultraviolet light with chemicals, or chemical carcinogens alone. With respect to the carotenoids, early experiments used pharmacological doses of carotenoids, but more recent reports indicate that relatively small doses can be effective. Inasmuch as these effects are seen with both provitamin A and nonprovitamin A carotenoids, it would appear that these effects are intrinsic to the carotenoid molecule, and not due to the metabolic conversion to retinoids. Partially on the basis of these observations, it has been suggested that the micronutrients may function as chemopreventive agents for reducing the risk of cancer in humans. Numerous human intervention studies are underway to test this hypothesis.

Animals↗
PubMed1993

Intestinal perfusion of beta-carotene in the ferret raises retinoic acid level in portal blood.

To determine whether beta-carotene (beta-C) can serve as a source of intestinally-derived retinoic acid (RA), either 15,15'-[14C]beta-C or unlabeled beta-C was perfused through 30 cm jejunal segments of ferrets in vivo. Portal vein blood was sampled periodically via an indwelling catheter. RA was identified in portal blood by comparing retention times in HPLC, by UV absorption, and by derivatization (methylation) and subsequent GC-MS analysis. The RA concentration in the portal blood increased 3-fold with perfusion of beta-C (P < 0.05), and remained at 18 nmol/L during the perfusion of beta-C. The single peak of RA in HPLC was shown to consist of four separate peaks by GC-MS, which may be cis-trans isomers of RA. The concentration of RA in portal blood returned to the initial level (5 nmol/L) after a 2 h period of intestinal perfusion with 5% dextrose. Retinyl ester concentration in portal blood did not change before or after the perfusion, whereas retinol decreased significantly during the perfusion of beta-C. This study clearly indicates that a considerable quantity and number of polar metabolites, including RA, are formed from beta-C in the ferret intestine which are transported via the portal vein to the liver.

Animals↗