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Biomedical subjects

H L Newmark

Publications and source records attributed to H L Newmark.

At least 73 records · Page 4Linked to original sources
PubMed1984

A hypothesis for dietary components as blocking agents of chemical carcinogenesis: plant phenolics and pyrrole pigments.

Initiation of chemical carcinogenesis involves the intracellular formation of a highly reactive electrophile that can attack many chemical nucleophiles in the cell, including DNA, a process that seems to be the central mechanism of initiation. Competing chemical nucleophiles in the cell, such as endogenous glutathione, can act as protecting or blocking agents against the attack on DNA. There are chemical substances in our food supply that may act as anticarcinogens or antimutagens by blocking or trapping ultimate-carcinogen electrophiles in a nucleophilic chemical reaction, to form innocuous products. A continuous input of these substances could serve as an additional buffer against DNA damage, supplementing the natural systems qualitatively and quantitatively. Certain plant phenolics can be effective inhibitors of chemical mutagens and/or carcinogens. Certain tetrapyrroles and porphyrins, both plant and animal, can also act as blocking agents. Both plant phenolics and porphyrins are primarily active against aromatic carcinogens. They are unlikely to be effective as blocking agents against nonaromatic carcinogens, or those with no aromatic groups in close proximity to the ultimate-carcinogen electrophilic group.

Animals↗
PubMed1984

Increased endogenous nitrosation in smokers.

Endogenous nitrosation of proline was investigated in smokers and nonsmokers. Volunteers consumed a volume of beetroot juice equivalent to 325 mg nitrate and, 1 h later, 500 mg proline. In separate experiments, volunteers ingested proline alone. Twenty-four-hour urines were collected and analysed for N-nitrosoproline. When proline was ingested alone, there was no significant difference in urinary N-nitrosoproline excretion between smokers and nonsmokers. When beetroot juice and proline were consumed, however, smokers produced approximately 2.5 times as much N-nitrosoproline as nonsmokers. Salivary nitrite levels of smokers and nonsmokers, both before and after consumption of beetroot juice, were not significantly different. Salivary thiocyanate levels were approximately 3.2. times higher in smokers than in nonsmokers. Our results suggest that the higher level of salivary thiocynate in smokers is responsible for the increased rate of endogenous nitrosation of proline in that group when compared with nonsmokers. Oxides of nitrogen in cigarette smoke do not appear to play a significant role.

Adult↗
PubMed1984

Colon cancer and dietary fat, phosphate, and calcium: a hypothesis.

Increased dietary fat was suggested to promote colon cancer by increasing the levels of free ionized fatty acids and bile acids in the colon contents. In the presence of calcium ions the irritating and toxic effects of the free acids on colon epithelial cells could be reduced by being converted to insoluble calcium soaps. The level of supplementary dietary calcium to supply adequate calcium and thus reduce the potential toxicity of dietary fat was considered.

Bile Acids and Salts↗
PubMed1984

N-nitrosation of proline in smokers and nonsmokers.

Endogenous nitrosation of proline was investigated in smokers and nonsmokers. Volunteers consumed a volume of beet juice equivalent to 325 mg nitrate, and 1 hour later they consumed 500 mg proline. In separate experiments volunteers ingested proline alone. Twenty-four-hour urine samples were collected and analyzed for N-nitrosoproline. When proline alone was ingested, there was no significant difference in urinary nitrosoproline excretion between smokers and nonsmokers. When beet juice and proline were consumed, however, smokers produced approximately 2.5 times as much N-nitrosoproline as nonsmokers. Salivary thiocyanate levels were approximately 3.2 times higher in smokers compared to those in nonsmokers. Salivary nitrite levels of smokers and nonsmokers, either before or after beet juice consumption, were not different. Salivary nitrate concentrations, however, were higher in nonsmokers than in smokers after beet juice consumption but not before. Our results suggest that the higher level of salivary thiocyanate in smokers is responsible for the increased rate of endogenous nitrosation of proline in this group compared to the rate in nonsmokers. Nitrosating agents in cigarette smoke do not appear to play a significant role.

Adult↗
PubMed1983

Caffeic acid as an inhibitor of DMBA-induced chromosomal breakage in mice assessed by bone-marrow micronucleus test.

Female mice of hybrid strain B6C3F1, 8-10 weeks old, were fed on powdered food with or without 2% caffeic acid. After one week on these diets, some of each group of mice were injected i.p., with 7,12-dimethyl benz[a]anthracene (25 mg/kg) dissolved in dimethyl disulfoxide. In the course of separate experiments, bone-marrow samples were taken at various intervals after injection for analysis in the micronucleus assay. From each mouse 500 polychromatic erythrocytes were scored to determine the frequency with micronuclei. At the time at which the maximum response was observed, which differed between experiments, the frequency of micronuclei induced by DMBA was reduced by 50% by the presence of caffeic acid. Caffeic acid (3,4-dihydroxy cinnamic acid) is widely distributed in plant materials in both free and combined forms and, as such, is a component of the human diet. Our results suggest that caffeic acid provides significant protection against the genotoxicity of DMBA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Inhibition of the mutagenicity of bay-region diol-epoxides of polycyclic aromatic hydrocarbons by phenolic plant flavonoids.

Myricetin, robinetin and luteolin inhibited the mutagenic activity resulting from the metabolic activation of benzo[a]-pyrene and (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]-pyrene by rat liver microsomes. These naturally occurring plant flavonoids and seventeen additional flavonoids and related derivatives with phenolic hydroxyl groups inhibited the mutagenic activity of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), which is an ultimate mutagenic and carcinogenic metabolite of benzo[a]pyrene. Several flavonoids without phenolic hydroxyl groups or with methylated phenolic hydroxyl groups were inactive. The mutagenic activity of 0.05 nmol of BP 7,8-diol-9,10-epoxide-2 towards strain TA 100 of S. typhimurium was inhibited 50% by incubation of the bacteria and the diol-epoxide with myricetin (2 nmol), robinetin (2.5 nmol), luteolin (5 nmol), quercetin (5 nmol), 7-methoxyquercetin (5 nmol), rutin (5 nmol), quercetin (5 nmol), delphinidin chloride (5 nmol), morin (10 nmol), myricitrin (10 nmol), kaempferol (10 nmol), diosmetin (10 nmol), fisetin (10 nmol), or apigenin (10 nmol). Considerably less antimutagenic activity was observed for dihydroquercetin, naringenin, robinin, D-catechin, genistein, kaempferide and chrysin. Pentamethoxyquercetin, tangeretin, nobiletin, 7,8-benzoflavone, 5,6-benzoflavone, and flavone, which lack free phenolic groups, were inactive. The antimutagenic activity of hydroxylated flavonoids results from their direct interaction with B[a]P 7,8-diol-9,10-epoxide-2 since the rate of disappearance of the diol-epoxide from cell-free solutions in 1:9 dioxane:water was markedly stimulated by myricetin, robinetin and quercetin. Myricetin was a highly potent inhibitor of the mutagenic activity of bay-region diol-epoxides of benzo[a]pyrene, dibenzo[a,h]pyrene and dibenzo[a,i]pyrene, but higher concentrations of myricetin were needed to inhibit the mutagenicity of the chemically less reactive benzo[a]pyrene 4,5-oxide and bay region diol-epoxides of benz[a]anthracene, chrysene and benzo[c]phenanthrene.

Animals↗
PubMed1983

Calcium ameliorates the toxic effect of deoxycholic acid on colonic epithelium.

The effect of a deoxycholic acid instillation on colonic epithelium was investigated and compared with the effect of an intervention scheme in which deoxycholic acid (DCA) treated mice received oral supplements of calcium lactate. The morphology of colonic tissue exposed to DCA was markedly affected when compared to that of untreated controls. Inflammation, edema, and necrosis preceded elevated numbers of mitotic figures appearing 24 h to 48 h after DCA treatment. Proliferative activity as measured by tritiated thymidine uptake and autoradiography was increased 2.5-fold in colonic crypts of DCA treated mice. In contrast mice receiving multiple oral supplements of calcium lactate showed minimal tissue necrosis due to DCA administration and the frequency of mitotic events and cellular proliferation activity remained similar to levels seen in untreated controls. Sequestration of bile acids by calcium salts may provide a scheme for inhibiting the untoward effects of bile acids on the colonic epithelium and a mechanism for blocking the reported co-carcinogenic activity of these agents.

Animals↗
PubMed1983

Nuclear aberrations as a short-term test for genotoxicity to the colon: evaluation of nineteen agents in mice.

The genotoxicity of 16 agents including several hydrazines, nitrosamines, aromatic amines, polycyclic hydrocarbons, and other related compounds and three known inhibitors of carcinogenesis was assessed in the murine colonic nuclear aberration assay. Of the seven agents considered positive for colonic DNA damage, five were large bowel carcinogens. All structural analogues of the intestinal carcinogens that are tumorigenic for other organs, with the exception of benzo[a]pyrene, were negative in the colonic nuclear aberration assay as were all noncarcinogens tested. The metabolic inhibitor disulfiram completely inhibited 1,2-dimethylhydrazine-induced colonic nuclear damage, while inhibition was less marked for the antioxidants butylated hydroxyanisole and caffeic acid. The versatility of the assay as an indicator of colonic genotoxicity resulting from carcinogen exposure is discussed.

1,2-Dimethylhydrazine↗
PubMed1982

Mechanism of the inhibition of mutagenicity of a benzo[a]pyrene 7,8-diol 9,10-epoxide by riboflavin 5'-phosphate.

Riboflavin 5'-phosphate (flavin mononucleotide; FMN) inhibits the mutagenicity of (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P diol epoxide), the only known ultimate carcinogenic metabolite of benzo[a]pyrene. Coincubation of 10, 25, and 50 nmol of FMN with strain TA100 of histidine-dependent Salmonella typhimurium inhibits the mutagenicity of 0.05 nmol of the diol epoxide by 50, 70, and 90%, respectively. Ribose 5-phosphate and riboflavin show no significant effects at comparable doses. Reaction of B[a]P diol epoxide with FMN in aqueous solution at neutral pH produces only tetraols, with no evidence for covalent adducts. At pH 7 the rate of hydrolysis of B[a]P diol epoxide in dioxane/water, 1:9 (vol/vol), at 25 degrees C is increased more than 10-fold in the presence of 100 muM FMN. Spectrophotometric studies and quantitative rate data for the reaction of the diol epoxide with FMN indicate that a complex is formed between the diol epoxide and the flavin moiety of FMN (Ke = 1,400-3,400 M-1) prior to general acid-catalyzed hydrolysis of the epoxide to tetraols by the phosphate monoanion of FMN. Comparable concentrations of ribose 5-phosphate and riboflavin do not significantly increase the rate of hydrolysis, although evidence for complex formation between riboflavin and the diol epoxide is observed. General acid-catalyzed hydrolysis of bay-region polycyclic hydrocarbon diol epoxides by compounds that have a high affinity for these ultimate carcinogens represents a potentially useful way of inhibiting their carcinogenic activity.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1982

Inhibition of the mutagenicity of bay-region diol epoxides of polycyclic aromatic hydrocarbons by naturally occurring plant phenols: exceptional activity of ellagic acid.

Ferulic, caffeic, chlorogenic, and ellagic acids, four naturally occurring plant phenols, inhibit the mutagenicity and cytotoxicity of (+/-)-7beta,8alpha-dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]P 7,8-diol-9,10-epoxide-2), the only known ultimate carcinogenic metabolite of benzo[a]pyrene. The mutagenicity of 0.05 nmol of B[a]P 7,8-diol-9,10-epoxide-2 in strain TA100 of Salmonella typhimurium is inhibited 50% by incubation of the bacteria and the diol epoxide with 150 nmol of ferulic acid, 75 nmol of caffeic acid, 50 nmol of chlorogenic acid or, most strikingly, 1 nmol of ellagic acid in the 0.5-ml incubation mixture. A 3-nmol dose of ellagic acid inhibits mutation induction by 90%. Ellagic acid is also a potent antagonist of B[a]P 7,8-diol-9,10-epoxide-2 in Chinese hamster V79 cells. Mutations to 8-azaguanine resistance induced by 0.2 muM diol epoxide are reduced by 50% when tissue culture media also contains 2 muM ellagic acid. Similar to results obtained with the bacteria, ferulic, caffeic, and chlorogenic acids are approximately two orders of magnitude less active than ellagic acid in the mammalian cell assay. The antimutagenic effects of the plant phenols result from their direct interaction with B[a]P 7,8-diol-9,10-epoxide-2, because a concentration-dependent increase in the rate of diol epoxide disappearance in cell-free solutions of 1:9 dioxane/water, pH 7.0, is observed with all four phenols. In parallel with the mutagenicity studies, ellagic acid is 80-300 times more effective than the other phenols in accelerating the disappearance of B[a]P 7,8-diol-9,10-epoxide-2. Ellagic acid at 10 muM increases the disappearance of B[a]P 7,8-diol-9,10-epoxide-2 by approximately 20-fold relative to the spontaneous and hydronium ion-catalyzed hydrolysis of the diol epoxide at pH 7.0. Ellagic acid is a highly potent inhibitor of the mutagenic activity of bay-region diol epoxides of benzo[a]pyrene, dibenzo[a,h]pyrene, and dibenzo[a,i]pyrene, but higher concentrations of ellagic acid are needed to inhibit the mutagenic activity of the chemically less reactive bay-region diol epoxides of benz[a]anthracene, chrysene, and benzo[c]phenanthrene. These studies demonstrate that ellagic acid is a potent antagonist of the adverse biological effects of the ultimate carcinogenic metabolites of several polycyclic aromatic hydrocarbons and suggest that this naturally occurring plant phenol, normally ingested by humans, may inhibit the carcinogenicity of polycyclic aromatic hydrocarbons.

Animals↗
PubMed1980

The influence of ascorbic acid and DL-alpha-tocopherol on the formation of nitrosamines in an in vitro gastrointestinal model system.

The nitrosation of aminopyrine (4.3 mmol/l) and dimethylamine (4.3 mmol/l) by nitrite (4.3 mmol/l) were studied over the pH range 6-8 in a system containing bile acids and lipid. Both amines were nitrosated to form N-nitrosodimethylamine. The nitrosation of aminopyrine and, to a greater extent, dimethylamine, is enhanced by bile acids. The simultaneous incorporation of ascorbic acid (8.6 mmol/l) and dl-alpha-tocopherol (4.3 mmol/l) was found to be effective in preventing the nitrosation of these two amines. dl-alpha-Tocopheryl acetate was found to be an ineffective blocking agent in this in vitro system.

Aminopyrine↗
PubMed1979

Ascorbic acid and vitamin B12.

Using extraction procedures in which the extracted vitamin B12 was protected by cyanide or metabisulfite, several investigators found no change in vitamin B12 when meals were incubated in the presence of ascorbic acid for 30 minutes at 37 degrees C. A previous report suggested degradation of vitamin B12 under these conditions, but this was apparently caused by incomplete protection of the extracted vitamin B12 in the assay procedure. If incubation at 37 degrees C for 30 minutes is a laboratory mimic of the gastric environment, one must conclude that high doses of ascorbic acid do not affect the stability of vitamin B12 in vivo.

Ascorbic Acid↗
PubMed1978

Alpha-tocopherol: uses in preventing nitrosamine formation.

alpha-Tocopherol has been evaluated as a nitrite scavenger for the prevention of nitrosamine formation in a model system and under practical conditions. alpha-Tocopherol was found to react with nitrosating agents in both lipophilic and aqueous environments. The use of alpha-tocopherol was shown to inhibit aminopyrene-nitrite induced hepatotoxicity in rats and to reduce the amount of NDMA formed in cigarette smoke. Of primary interest is the finding of a significant reduction of NPYR formation in fried bacon. Nitrosamine inhibition was greater with alpha-tocopherol used in combination with sodium ascorbate than with sodium ascorbate alone.

Animals↗
PubMed1976

Stability of vitamin B12 in the presence of ascorbic acid.

Experiments were performed in two independent laboratories, each using their own meal preparations which were exactly similar in composition to the meals described by Herbert and Jacob (J. Am. Med. Assoc. 230:241, 1974), in order to check their report that incubating meals (portions of daily food intake by man) of "modest" or "high" vitamin B12 content with increasing levels of added L-ascorbic acid (vitamin C) produced increasing destruction of vitamin B12. The present studies were performed with standardized and official methods. Vitamin B12 was determined microbiologically and by radioassay method. The results showed that 1) the vitamin B12 contents of these meals were in general agreement with values calculated from the literature for the foods involved, 2) the values obtained were manyfold higher than those reported by Herbert and Jacob, and 3) there was no deleterious effect of added ascorbic acid on the vitamin B12 content of meals, contrary to their published results.

Ascorbic Acid↗
PubMed1975

Biopharmaceutic factors in parenteral administration of vitamin E.

When properly formulated, micellar-type aqueous dispersions of tocopheryl acetate are administered intravenously or intramuscularly to dogs, the rate-limiting step in the bioavailability of the physiologically active free tocopherol is the rate of hydrolysis of the acetate ester. A similar dispersion of free tocopherol yields blood levels of tocopherol many fold higher than those obtained with the acetate ester after intravenous injection and also yields much greater increases in blood levels of free tocopherol after intramuscular injection than the acetate ester formulation, particularly in the early period after the dose.

Acetates↗