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Biomedical subjects

N I Krinsky

Publications and source records attributed to N I Krinsky.

At least 55 records · Page 3Linked to original sources
PubMed1993

Effects of carotenoids on cells.

When added to cells, carotenoids display a variety of properties, including inhibition of mutagenesis, genotoxicity, malignant transformation, and growth of tumor cells. In addition, carotenoids increase cell-cell communication, and may have direct effects as cellular antioxidants.

Animals↗
PubMed1993

Retinoic acid regulates retinol metabolism via feedback inhibition of retinol oxidation and stimulation of retinol esterification in ferret liver.

When the plasma concentration of retinoic acid is increased, there is an accompanying reduction of circulating levels of retinol, suggesting that retinoic acid may have a regulatory effect on retinol metabolism in vivo. To determine which specific step(s) of retinol metabolism might be regulated by retinoic acid, retinol was incubated with ferret liver microsomes or cytosol with retinoic acid in vitro. Incubating the microsomal fraction with retinoic acid resulted in a dose-dependent (up to 0.5 mumol/L) decrease in the formation of retinal. On the contrary, no retinoic acid inhibitory effect was observed on retinal synthesis in the cytosol incubation, or in the cytosol plus microsome incubation. However, when retinoic acid was added to the cytosolic incubation mixture in the presence of the retinal oxidative inhibitor, citral, a dose-dependent inhibition of retinal synthesis was observed. Furthermore, the effect of retinoic acid on retinyl ester metabolism in ferret liver was studied by using endogenous retinyl esters of ferret liver as the substrate. When retinoic acid was added to the incubation mixture of microsomes plus cytosol, small, nonsignificant increases in retinol and retinyl esters were observed. When retinoic acid was added in the presence of citral, both the inhibition of retinol oxidation and the stimulation of retinol esterification were dose dependent up to approximately 0.3 mumol/L and then remained the same up to 1.0 mumol/L. These data strongly suggest that retinoic acid has a regulatory effect on retinol metabolism in ferret liver, which may occur via feedback inhibition of retinol oxidation and stimulation of retinol esterification.

Animals↗
PubMed1992

beta-Carotene and alpha-tocopherol are synergistic antioxidants.

The possibility of a cooperative interaction between fat-soluble antioxidants is examined in a membrane model. A combination of beta-carotene and alpha-tocopherol results in an inhibition of lipid peroxidation significantly greater than the sum of the individual inhibitions. Our data provide the first evidence that beta-carotene can act synergistically with alpha-tocopherol as an effective radical-trapping antioxidant in membranes.

Amidines↗
PubMed1992

Anticarcinogenic activities of carotenoids in animals and cellular systems.

A large number of studies have indicated that carotenoid pigments act as anticarcinogenic agents in animals treated with either ultraviolet light, ultraviolet light with chemicals, or with chemical carcinogens alone. Although pharmacological doses of cartenoids were used in the early experiments, more recent evidence indicates that relatively small doses can be effective. These studies have been complemented by investigations in bacteria and mammalian tissue, either in cell culture or in organ culture, where it has been demonstrated that various carotenoid pigments can prevent mutagenesis, genotoxic effects, or malignant transformation. It would appear that these effects are intrinsic to the carotenoid molecule, and not necessarily due to the metabolic conversion to retinoids. Partially based on these observations, it has been suggested that carotenoid pigments may function as chemopreventive agents for reducing the risk of cancer in humans. Numerous studies are underway to test this hypothesis.

Animals↗
PubMed1992

Retinoic acid can be produced from excentric cleavage of beta-carotene in human intestinal mucosa.

The hypothesis that retinoic acid (RA) is produced from the excentric cleavage of beta-carotene was tested in human intestinal homogenates in vitro. Significant amounts of RA were identified by HPLC and derivatization after incubation of intestinal mucosal homogenates with retinal, beta-carotene, or beta-apocarotenals at 37 degrees C for 60 min. RA formation was inhibited, in a dose-dependent fashion, when retinal was incubated in the presence of 0.1-3.0 mM citral (3,7-dimethyl-2,6-octadienal) under identical experimental conditions. The formation of RA from both beta-carotene and beta-apocarotenals was dose and time dependent and RA was the major metabolite of both beta-apo-8'-carotenal and beta-apo-12'-carotenal after the incubation. However, citral (0.1 to 4 mM) did not inhibit the formation of beta-apocarotenals and RA from 2 microM beta-carotene (P greater than 0.05), which proves the existence of an excentric cleavage mechanism for beta-carotene conversion into retinoids. Furthermore, RA formation from both beta-apo-8'-carotenal and beta-apo-12'-carotenal in human intestinal homogenate occurred in the presence of citral, which demonstrates that RA can be produced from excentric cleavage of beta-carotene via a series of beta-apocarotenals as intermediates.

Acyclic Monoterpenes↗
PubMed1992

Astaxanthin and canthaxanthin are potent antioxidants in a membrane model.

When the conjugated keto-carotenoids, either astaxanthin or canthaxanthin, are added to rat liver microsomes undergoing radical-initiated lipid peroxidation under air, they are as effective as alpha-tocopherol in inhibiting this process. This contrasts with the effect of beta-carotene, which is a much less potent antioxidant when added in this system, without the addition of other antioxidants.

Adjuvants, Immunologic↗
PubMed1992

Effects of beta-carotene and alpha-tocopherol on radical-initiated peroxidation of microsomes.

Rat liver microsomal membranes were exposed to either beta-nicotinamide adenine dinucleotide phosphate (NADPH), adenosine 5'-diphosphate (ADP), and Fe+3 or to azocompounds, and the antioxidant activities of beta-carotene and alpha-tocopherol were studied. Lipid peroxidation was monitored either by malondialdehyde (MDA) formation in the thiobarbituric acid assay at 535 nm or by hydroperoxide formation at 234 nm, after high-pressure liquid chromatography (HPLC) separation of phospholipid hydroperoxides. The radical initiators, water-soluble 2,2'-azobis(2-amidinopropane) (AAPH) and lipid-soluble 2,2'-azobis(2,4-dimethylvaleronitrile (AMVN), when thermally decomposed at 37 degrees C under air, produced a constant rate of lipid peroxidation in microsomes and lag times inversely related to their concentrations. Using 25 mM AAPH, beta-carotene suppressed lipid peroxidation at a concentration of 50 nmol/mg protein; using 24 mM AMVN, an inhibition of MDA formation was observed at a concentration of only 5 nmol/mg protein. Inhibition by beta-carotene did not produce a clearly defined lag phase. During AAPH-induced lipid peroxidation, beta-carotene was consumed linearly, and high levels of the antioxidant were still present at the end of 45 min of incubation. Using NADPH/ADP/Fe+3, protection by beta-carotene was observed at 10 nmol/mg protein. alpha-Tocopherol effectively suppressed both MDA and hydroperoxide formation in a dose-dependent manner when either NADPH/ADP/Fe+3 or azocompounds were used. These effects were observed at very low concentrations of the added alpha-tocopherol, ranging from 2 to 3 nmol/mg protein. When the lag times were measurable (AAPH and AMVN), they were directly proportional to the concentration of alpha-tocopherol and revealed the presence of endogenous antioxidants in the microsomal membranes. Different temporal relationships between the loss of alpha-tocopherol and lipid peroxidation were observed in relation to the prooxidant used. A substantial depletion of about 70% of endogenous alpha-tocopherol preceded the propagation phase when induced by the azocompounds, while only 20% of antioxidant disappeared at the beginning of the peroxidation when induced by NADPH/ADP/Fe+3. Although our results show that both beta-carotene and alpha-tocopherol suppress the peroxidation of microsomal membranes, their antioxidant efficacy is influenced by several factors, including the type of radical initiator involved and the site and rate of radical production.

Amidines↗
PubMed1992

Intestinal uptake and lymphatic absorption of beta-carotene in ferrets: a model for human beta-carotene metabolism.

To determine the appropriateness of the ferret as a model for human beta-carotene (beta-C) metabolism, we have perfused both 15,15'-beta-[14C]C and unlabeled beta-C through the upper 30-cm portion of the small intestine of ferrets in vivo. The effluents of a mesenteric lymph duct cannulation and a common bile duct cannulation, as well as portal vein blood periodically sampled via an indwelling catheter, were collected. Ten percent (9.5 +/- 0.06%) of the total administered beta-C was taken up by the intestine after a 4-h perfusion. Of the radioactivity taken up, 68.6 +/- 6.5% remained in the intestinal mucosa, 3.2 +/- 0.2% was recovered in the lymph, and 28.2 +/- 6.5% (calculated) was absorbed via the portal system. The total uptake/absorption of beta-C was 12.9 +/- 6.8 nmol.h-1.30 cm intestine-1. Large amounts of unchanged beta-C and relatively small amounts of both beta-apo-12'-carotenal and beta-apo-10'-carotenal were isolated in the intestinal mucosa after a 4-h perfusion with beta-C. Considerable amounts of metabolites more polar than retinol were formed and comprised 35% of the total radioactivity recovered in the intestinal mucosa. Polar metabolites were absorbed mostly into the portal venous system, whereas retinol and retinyl esters were absorbed mainly into the mesenteric lymph. Of the total absorbed radioactivity in lymph, 10 +/- 1.0% appeared as unchanged beta-C, with peak absorption occurring at 3 h after beginning the perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1992

Mechanism of action of biological antioxidants.

More and more diseases have been proposed to have a radical or oxidant involvement. Although in most cases we do not know if this involvement is a cause or a result of the disease process, it is still valuable to learn about those compounds or enzymes that might block, inhibit, or prevent radical-initiated reactions. Therefore, it becomes increasingly important to understand which compounds can function as antioxidants, where they are located in the body, and what their mechanism of action might be. As we increase our knowledge in these areas, we will have a better opportunity to propose interventions that might suppress or even reverse some of the ravages of oxidant-based diseases in humans.

Animals↗
PubMed1991

Characterization of beta-apo-13-carotenone and beta-apo-14'-carotenal as enzymatic products of the excentric cleavage of beta-carotene.

Two new products from the incubation of beta-carotene with intestinal mucosa homogenates of human, monkey, ferret, and rat were isolated using high-performance liquid chromatography (HPLC). Identification by comparing retention times in HPLC, by monitoring ultraviolet/visible spectra, by reduction to corresponding alcohol, by oxime formation, and by mass spectrometry demonstrated that they are beta-apo-13-carotenone and beta-apo-14'-carotenal. These compounds were not found in incubations done without intestinal homogenates or with disulfiram as an inhibitor. Under standard incubation conditions, these products increased linearly for 60 min and up to a protein concentration of 1.5 mg/mL and increased along with increasing concentrations of beta-carotene. Therefore, they are enzymatic cleavage products from beta-carotene. The formation of the beta-apo-13-carotenone and beta-apo-14'-carotenal provides direct evidence for an enzymatic excentric cleavage mechanism.

Animals↗
PubMed1991

Enzymatic conversion of beta-carotene into beta-apo-carotenals and retinoids by human, monkey, ferret, and rat tissues.

Whether the conversion of beta-carotene into retinoids involves an enzymatic excentric cleavage mechanism was examined in vitro with homogenates prepared from human, monkey, ferret, and rat tissue. Using high-performance liquid chromatography, significant amounts of beta-apo-12'-, -10'-, and -8'-carotenals, retinal, and retinoic acid were found after incubation of intestinal homogenates of the four different species with beta-carotene in the presence of NAD+ and dithiothreitol. No beta-apo-carotenals or retinoids were detected in control incubations done without tissue homogenates. The production of beta-apo-carotenals was linear for 30 min and up to tissue protein concentrations of 1.5 mg/ml. The rate of formation of beta-apo-carotenals from 2 microM beta-carotene was about 7- to 14-fold higher than the rate of retinoid formation in intestinal homogenates, and the rate of beta-apo-carotenal production was fivefold greater in primate intestine vs rat or ferret intestine (P less than 0.05). The amounts of beta-apo-carotenals and retinoids formed were markedly reduced when NAD+ was replaced by NADH, or when dithiothreitol and cofactors were deleted from the incubation mixture. Both beta-apo-carotenal and retinoid production from beta-carotene were inhibited completely by adding disulfiram, an inhibitor of sulfhydryl-containing enzymes. Incubation of beta-carotene with liver, kidney, lung, and fat homogenates from each species also resulted in the appearance of beta-apo-carotenals and retinoids. The identification of three unknown compounds which might be excentric cleavage products is ongoing. These data support the existence of an excentric cleavage mechanism for beta-carotene conversion.

Animals↗
PubMed1991

Characterization of products formed during the autoxidation of beta-carotene.

The anticarcinogenic action of carotenoids such as beta-carotene has been frequently ascribed to their antioxidant properties. However, very little is actually known about the nature of the antioxidant reaction or the products that are formed. beta-Carotene was exposed to either spontaneous autoxidation conditions or to radical-initiated autoxidation conditions. The products were separated by reverse-phase HPLC, and individual peaks were characterized with an on-line diode array detector. Carbonyl products were isolated and characterized by several procedures, including borohydride reduction to the corresponding alcohols, derivatization with O-ethyl-hydroxylamine to the corresponding O-ethyl-oximes of the carbonyls, and analysis by GC-MS. Under the conditions of the experiments, the formation of a homologous series of carbonyl products was demonstrated, including beta-apo-13-carotenone, retinal, beta-apo-14'-carotenal, beta-apo-12'-carotenal, and beta-apo-10'-carotenal. Several very hydrophobic compounds were formed, which have not been previously identified. In addition, the products of NaOCl-treatment of beta-carotene were analyzed, and shown to be significantly different from the autoxidation products. This type of product analysis should be useful in determining the nature of the oxidants reacting with beta-carotene in vivo.

Antioxidants↗
PubMed1991

The inhibition of radical-initiated peroxidation of microsomal lipids by both alpha-tocopherol and beta-carotene.

Rat liver microsomal lipids in hexane solution were exposed to the lipid-soluble radical initiator, azobis-isobutyronitrile (AIBN), and the antioxidant activities of alpha-tocopherol and beta-carotene have been compared. Lipid peroxidation was monitored both by conjugated diene formation at 233 nm, and by malondialdehyde (MDA) formation in the thiobarbituric acid assay at 535 nm. Diene formation was continuous for at least 120 min in the presence of 85 micrograms/ml lipid and 4 mM AIBN. Both alpha-tocopherol and beta-carotene acted as chain-breaking antioxidants, suppressing lipid peroxidation and producing an induction period at concentrations as low as 0.5 and 8 microM, respectively. When both of these lipid-soluble antioxidants were present together, the oxidation was strongly suppressed and the induction period was the sum of the individual antioxidants, alpha-Tocopherol and beta-carotene also inhibited MDA generation. In the presence of 170 micrograms/ml lipid and 8 mM AIBN, beta-carotene exhibited an IC50 of 1.1 microM and inhibited completely at 15 microM. Using beta-carotene, an induction period was observed, although much less pronounced than with alpha-tocopherol. Furthermore, beta-carotene inhibited MDA production in a concentration-dependent manner and exhibited an IC50 of 50 microM. In addition, added beta-carotene delayed the radical-initiated destruction of the endogenous alpha-tocopherol and gamma-tocopherol in this system.

Animals↗