Biomedical subjects
R S Rivlin
Publications and source records attributed to R S Rivlin.
Abnormal taste preference for saccharin in hypothyroid rats.
Taste preferences for saccharin in concentrations ranging from 0.16 mM to 50 mM were determined in rats made hypothyroid with radioactive iodine and in their littermate controls. Hypothyroid rats demonstrated taste preferences for saccharin which were similar to those of controls only at very low (0.016 mM) or very high (49.0 mM) saccharin concentrations. At these concentrations of tastant, the preferences for tastant and water were similar to one another. At a concentration of 5.1 mM, preferences were also very similar in both groups but were very high. At intermediate saccharin concentrations of 1.1 and 3.0 mM, hypothyroid animals showed significantly lower percent preferences for the sweet tastant than did controls, mean +/- SEM (62.48 +/- 5.97 vs. 82.92 +/- 4.60, p = 0.0002) for the 1.1 mM concentration and (74.98 +/- 5.12 vs. 89.40 +/- 2.54, p = 0.0029) for the 3.0 mM concentration. These changes in taste preference for saccharin in hypothyroid rats were similar in direction and magnitude to those previously published by this laboratory using sucrose as the tastant. Thus, hypothyroid rats demonstrate abnormalities in taste preference for both the nonnutritive sweetener, sodium saccharin, as well as for the nutritive sweetener, sucrose.
Enhanced depletion of lens reduced glutathione Adriamycin in riboflavin-deficient rats.
The anticancer drug Adriamycin has photosensitizing properties which potentially may be detrimental to lens tissue. Since reduced glutathione (GSH) serves to protect lens from photo-oxidative stress and dietary riboflavin is required by glutathione reductase to regenerate GSH, we investigated whether Adriamycin intensifies the depletion of GSH levels in rat lens during dietary riboflavin deficiency. Three-week-old rats were divided into two groups. One group was fed a diet deficient in riboflavin (less than 1 ppm) and the other group was pair-fed a control diet containing adequate riboflavin (8.5 ppm). After 6-12 weeks of dietary treatment, half the animals in each dietary group received Adriamycin (8 mg/kg/day) intraperitoneally for 3 days. After killing the rats, lenses were removed, and GSH content and glutathione reductase activity were measured in freshly prepared homogenates. To determine the extent of systemic oxidative stress and the degree of riboflavin deficiency, glucose-6-phosphate dehydrogenase and glutathione reductase activities, respectively, were measured in erythrocytes. In lens of rats fed the riboflavin-sufficient diet, treatment with Adriamycin did not diminish GSH content or alter glutathione reductase activity. In confirmation of reports by others, lenses of animals fed the riboflavin-deficient diet had diminished GSH levels, lower basal glutathione reductase activity, and elevated glutathione reductase activity coefficients compared to those of animals pair-fed the control diet. The present study shows that in riboflavin-deficient rats, Adriamycin exacerbated the depletion of GSH but did not reduce further glutathione reductase activity. The implications of these findings are that nutritional deficiencies, in particular riboflavin deprivation, may pose a potential risk to lenticular tissue following Adriamycin treatment.
Dietary calcium and chronic diseases.
The Agricultural Revolution was almost certainly associated with a substantial decrease in human calcium intake. Calcium intakes typical of contemporary humans may well be inadequate for many individuals. Various slowly developing chronic disorders such as osteoporosis, hypertension, hyperlipidemia, and colon cancer may be induced or exaggerated by the current low level of dietary calcium intake in Western societies. We propose two hypotheses relating calcium intake to diverse diseases: first, the adaptation required to adjust to low intakes is inadequate to maintain critical components of cellular calcium regulation; second, the constant, forced adaptive response to low intake itself produces untoward consequences.
The clinical significance of micronutrients in relation to immune functions.
Explore the source record for details and available documents.
Dietary zinc deficiency decreases plasma concentrations of vitamin E.
Experiments were conducted to examine the effects of dietary zinc (Zn) upon plasma vitamin E (E) concentrations to test the hypothesis that there may be a significant dietary interaction between these two nutrients. Weanling female Sprague-Dawley rats were fed diets that were (i) Zn-deficient (less than 0.9 micrograms Zn/g diet) ad libitum; (ii) Zn-adequate (50.9 micrograms Zn/g diet), pair-fed to the Zn-deficient group; and (iii) Zn-adequate (50.9 micrograms Zn/g diet) ad libitum. Plasma E in Zn-deficient animals (4.02 +/- 1.20 micrograms/ml) was significantly reduced (P less than or equal to 0.05) compared with results in both Zn-adequate pair-fed (9.21 +/- 0.70 micrograms/ml) and Zn-adequate ad libitum-fed (9.47 +/- 0.90 micrograms/ml) animals. Zn deficiency in this model system also resulted in significant (P less than or equal to 0.05) reductions in femur and plasma Zn concentrations as well as in plasma retinol, plasma triglyceride, and plasma cholesterol concentrations. Plasma albumin and total plasma protein concentrations were normal in Zn-deficient animals. With dietary Zn deficiency, the decrease in plasma E appeared to be out of proportion to associated decreases in plasma triglyceride and plasma cholesterol concentrations. Since E is associated with plasma lipoproteins, these data suggest that lipid and/or E malabsorption may be a consequence of Zn deficiency. In response to increased dietary intake of E, increments of plasma E were lower in Zn-depleted than in Zn-adequate, pair-fed animals. These findings suggest that dietary Zn deficiency possibly may increase the nutritional requirement for E necessary to maintain adequate plasma concentrations.
Riboflavin deficiency and glutathione metabolism in rats: possible mechanisms underlying altered responses to hemolytic stimuli.
Riboflavin deficiency suppresses parasitic growth in malaria. Three possible mechanisms have been proposed previously to explain the survival advantage of riboflavin-deficient hosts: a) enhanced fragility of red blood cells (RBC), b) decreased formation of reticulocytes and/or c) decreased concentrations of reduced glutathione (GSH) and ATP. The validity of these proposed mechanisms was tested by investigating whether riboflavin deficiency alters the hemolytic response to three stimuli: hydrogen peroxide (H2O2), a hypotonic medium or ferriprotoporphyrin IX (FP). Reticulocyte counts and concentrations of ATP and GSH were also determined. The percentage of hemolysis induced by H2O2 or FP was significantly less in riboflavin-deficient than in control animals. By contrast, hemolytic response to a hypotonic medium was enhanced during riboflavin deficiency. Despite diminished activity of glutathione reductase and normal glutathione peroxidase activity during riboflavin deficiency, the erythrocyte concentration of GSH was increased over that in control animals. Concentrations of ATP and hemoglobin in erythrocytes as well as the reticulocyte count were unaltered during riboflavin deficiency. Thus, diminished malarial parasitemia in riboflavin-deficient animals occurs despite greater resistance of RBC to either H2O2- or FP-induced hemolysis, and in the presence of a normal reticulocyte count and erythrocytes ATP concentration. Results of this study raise the possibility that Plasmodium parasites have greater requirements for flavin coenzymes, GSH or ATP than those of host erythrocytes, which may explain the apparent protection of the riboflavin-deficient host from malaria.
Enhancement of adriamycin-induced mortality during riboflavin administration and riboflavin deficiency in rats.
Adriamycin-treated rats were monitored for survivorship while consuming a normal diet adequate in riboflavin, a normal diet and receiving daily high-dose injections of riboflavin-5'-phosphate (flavin mononucleotide, FMN), or a riboflavin-deficient diet. Each animal was compared to a corresponding pair-fed, saline-treated control. In Adriamycin-treated rats fed the normal chow diet alone, survivorship declined within 7 days and remained constant after 12 days to about 50%. Adriamycin-treated rats consuming the normal diet and injected with FMN initially showed similar survivorship; however, after 20 days survival fell to 14%. Adriamycin-treated, riboflavin-deficient rats showed within 5 days a precipitous decline in survivorship which leveled to 5%. These results suggest that during Adriamycin treatment, proper riboflavin nutriture may be a crucial determinant of survival.
Disturbances in the formation of FAD and covalently bound flavins in Novikoff hepatoma from riboflavin-deficient rats.
The incorporation of radiolabeled riboflavin into flavin mononucleotide, flavin adenine dinucleotide, and flavin covalently bound to protein was determined in Novikoff hepatoma grown in both riboflavin-deficient and normal chow-fed rats. In Novikoff hepatoma, the incorporation of [14C]riboflavin into covalently bound flavins relative to that into FAD was substantially greater than that in host liver, and the turnover rate of riboflavin was also accelerated in tumor compared with the liver. The magnitude of incorporation of [14C]riboflavin into each of the various flavin fractions was substantially greater in tumors from riboflavin-deficient animals than in tumors from control animals. These data support the hypothesis that in conditions of riboflavin deprivation, Novikoff hepatoma maintains the levels of the physiologically important flavin coenzymes at the expense of the free riboflavin fraction. The incorporation of riboflavin into covalently bound flavins relative to that into FAD is substantially greater in Novikoff hepatoma than in liver. Accordingly, covalently bound flavins are either present in greater amounts or regulated differently in tumor than in normal tissue. Because the flavin moiety cannot be reutilized, the covalently bound flavin fraction in Novikoff hepatoma theoretically should be able to sequester riboflavin and thereby deplete the body reserves of this vitamin when dietary intake is marginal.
Statement on vitamin and mineral supplements. The Joint Public Information Committee of the American Institute of Nutrition and the American Society for Clinical Nutrition.
Explore the source record for details and available documents.
Mechanisms underlying the differential effects of ethanol on the bioavailability of riboflavin and flavin adenine dinucleotide.
Chronic alcoholism is associated with a high prevalence of riboflavin deficiency. Experiments were designed in an animal model to determine whether ethanol alters selectively the absorption of riboflavin and flavin adenine dinucleotide (FAD), the predominant dietary form of the vitamin. Rats received by gavage a liver homogenate to which either [14C]riboflavin or [14C]FAD was added with either ethanol or isocaloric sucrose solutions. Ethanol markedly diminished the bioavailability of [14C]FAD to a greater degree than that of [14C]riboflavin. Corroboration of an ethanol-impaired intraluminal hydrolysis of FAD was provided by using everted jejunal segments and measuring mucosal uptake of [14C]riboflavin together with nonradiolabeled FAD. In subsequent studies with mucosal cell extracts, ethanol markedly inhibited activities of FAD pyrophosphatase and flavin mononucleotide (FMN) phosphatase. These findings suggest that dietary sources of riboflavin (FMN and FAD) are not absorbed as well in the presence of ethanol than are vitamin preparations containing riboflavin, which is utilized more readily.
Drugs that promote renal excretion of riboflavin.
Enhanced urinary excretion of vitamins induced by drugs is a major factor in development of vitamin deficiencies. In addition to increasing urinary excretion, drugs can induce vitamin deficiencies by altering their intestinal absorption, transport, storage, and/or metabolic conversions. Aside from drugs, other factors known to influence urinary excretion of vitamins include the level of the vitamin in the diet, the degree of tissue saturation of the vitamin, and the extent of protein binding of the vitamin. Alterations in various aspects of flavin metabolism have been observed following administration of certain drugs, namely, antimalarial, antimicrobial, anticancer, and some tricyclic antidepressant and antipsychotic agents. Of these drugs, boric acid and its derivatives as well as the antipsychotic agent, chlorpromazine, have been shown to promote riboflavinuria in both animals and man. Boric acid complexes with the polyhydroxyl ribitol side chain of riboflavin and greatly increases its water solubility. Individuals who have accidentally consumed boric acid or one of its derivatives excrete high levels of riboflavin within the first 24 to 48 hours following ingestion. The phenothiazine ring of chlorpromazine and the isoalloxazine ring of riboflavin have a number of structural features in common and have been shown to form a molecular complex in vitro. In animals treated for a 3- and 7-week period with chlorpromazine, urinary levels of riboflavin are twice that of pair-fed, saline-treated animals. Recent studies have extended these findings to humans. The administration of certain agents, either therapeutic or toxic, which enhance urinary riboflavin excretion may be of particular concern for high-risk patients who are already nutritionally compromised because of illness or disease.
New approaches to the possible prevention of side effects of chemotherapy by nutrition.
In an effort to develop new methods for preventing side effects of chemotherapy, the authors initiated studies to determine whether Adriamycin (doxorubicin) inhibits the metabolism of riboflavin (vitamin B2). Adriamycin has been shown to form a 1:1 stoichiometric complex with riboflavin, as well as to compete for binding to tissue proteins. Adult rats treated with Adriamycin in clinically relevant doses were compared to control animals in ability to convert riboflavin into flavin adenine dinucleotide (FAD), the active flavin coenzyme derivative, in heart, skeletal muscle, liver, and kidney. Rats treated with Adriamycin exhibited diminished formation of carbon 14 (14C)FAD in skeletal muscle to nearly 50% that of controls, and in heart to about 70% to 80% of controls. Under these conditions, (14C)FAD formation in liver and kidney was largely unaffected by Adriamycin. In preliminary studies, riboflavin-deficient animals treated with Adriamycin had accelerated mortality rates compared to those of food restricted controls treated with similar doses of Adriamycin. The data as a whole suggest a potential mechanism for Adriamycin-induced cardiac and skeletal myopathy, i.e., inhibition of synthesis of FAD, a flavin coenzyme which is involved in electron transport, lipid metabolism, and energy generation. These findings in an animal model raise the possibility that defects of riboflavin nutriture, either dietary or drug-induced, may be a determinant of Adriamycin toxicity. Further studies are required to explore the potential for preventing side effects due to Adriamycin by administration of this vitamin.
Malaria chemotherapy through interference of riboflavin metabolism.
Explore the source record for details and available documents.
Riboflavin.
Riboflavin deficiency diminishes the rate of growth of spontaneous tumors in experimental animals but enhances the carcinogenicity of specific drugs such as the azo dyes, which are degraded by a microsomal hydroxylase system requiring riboflavin. Human esophageal cancer has been epidemiologically associated with riboflavin deficiency, but the precise role of riboflavin in this tumor remains to be defined. Riboflavin nutriture influences epithelial integrity, tissue flavin concentrations, rates of prostaglandin biosynthesis, and glutathione metabolism, each of which may have implications for carcinogenesis.
Inhibition by chlorpromazine of thyroxine modulation of flavin metabolism in liver, cerebrum and cerebellum.
In livers of adult rats that have been treated with thyroxine, the rate of incorporation of radiolabeled riboflavin into both flavin adenine dinucleotide (FAD) and FAD covalently attached to specific apoflavoenzymes was enhanced markedly. By contrast, thyroxine diminished riboflavin incorporation into FAD in cerebrum and cerebellum but continued to enhance incorporation into the covalently bound fraction of FAD. Diminished net incorporation of riboflavin into FAD in brains of adult rats may reflect increased utilization of this fraction for covalent attachment into specific apoflavoenzymes rather than down regulation of the FAD biosynthetic enzymes, flavokinase and FAD pyrophosphorylase, inasmuch as covalent attachment of FAD occurs subsequent to the formation of FAD. The psychotropic drug, chlorpromazine, over a wide dose range, exerted an inhibitory effect on both incorporation of riboflavin into FAD and the utilization of FAD for incorporation into covalently bound flavoenzymes in liver, cerebrum, and cerebellum. Thus, chlorpromazine inhibition of FAD metabolism occurred regardless of the direction of the thyroxine effect and was compatible with an observed inhibitory effect by this drug upon the flavin biosynthetic enzymes.
Effects of riboflavin deficiency upon prostaglandin biosynthesis in rat kidney.
The effects of riboflavin deficiency on the activity in vitro of prostaglandin synthetase were determined in rat kidney homogenates. For a period of two to five months, weaning rats were fed either a diet deficient in riboflavin or equal amounts of a diet identical in composition except for the addition of riboflavin at four times the RDA for this vitamin. In further experiments, each group of rats was treated for 10 days with either an inhibitor of cyclooxygenase (flurbiprofen) or buffer. Following sacrifice, prostaglandin biosynthesis in vitro was measured both in the absence and presence of reduced glutathione, and subsequently in the presence of reduced glutathione with and without flurbiprofen. Reaction products were extracted from supernatant solutions with diethylether, and the PGE2 and PGF2 alpha formed were measured by radioimmunoassay. Dietary riboflavin deficiency increased biosynthesis rates in vitro of both PGE2 and PGF2 alpha in rat renal medulla and papilla. When both control and riboflavin deficient rats were treated with flurbiprofen for a 10 day period, PGE2 biosynthesis in vitro was markedly inhibited. This inhibition of PGE2 biosynthesis was partially overcome by the addition of reduced glutathione in vitro. The addition of flurbiprofen in vitro to samples containing reduced glutathione prevented the restoration of PGE2 biosynthesis by the latter. The rate of prostaglandin biosynthesis in kidney homogenates from riboflavin deficient rats remained higher than that of controls with each experimental manipulation. These data in their entirety suggest a possible role for riboflavin in the regulation of renal prostaglandin biosynthesis in the rat.
Relation of riboflavin nutriture in healthy elderly to intake of calcium and vitamin supplements: evidence against riboflavin supplementation.
The status of riboflavin nutriture was evaluated in 24 healthy elderly female residents of a private, nonprofit facility for the care of ambulatory elderly. Riboflavin intake by history was greater than or equal to the recommended dietary allowances (RDA) for this nutrient in all but three subjects, and the average intake in the group as a whole was 50% greater than the RDA. Confirmatory of the findings by history, the status of riboflavin nutriture was excellent in nearly all subjects as evaluated by urinary riboflavin excretion and erythrocyte glutathione reductase activity coefficient. By contrast, calcium intake was greater than or equal to the RDA in ony four of the 24 subjects. The adequacy of calcium intake was found to depend upon a sufficiently high percentage of the total dietary intake of riboflavin being derived from milk and dairy products. It was observed that individual calcium intakes were less than 80% of the RDA unless 40% or more of the total intake of riboflavin was derived from milk and dairy products rather than from other food sources. In those subjects taking daily supplementation with a single multivitamin tablet containing low levels of riboflavin, the total intake of riboflavin and its urinary excretion were increased similarly, suggesting that even small amounts of riboflavin are not retained by elderly subjects consuming a diet adequate in riboflavin.(ABSTRACT TRUNCATED AT 250 WORDS)