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Biomedical subjects

B N Ames

Publications and source records attributed to B N Ames.

At least 145 records · Page 8Linked to original sources
PubMed1990

Dietary pesticides (99.99% all natural).

The toxicological significance of exposures to synthetic chemicals is examined in the context of exposures to naturally occurring chemicals. We calculate that 99.99% (by weight) of the pesticides in the American diet are chemicals that plants produce to defend themselves. Only 52 natural pesticides have been tested in high-dose animal cancer tests, and about half (27) are rodent carcinogens; these 27 are shown to be present in many common foods. We conclude that natural and synthetic chemicals are equally likely to be positive in animal cancer tests. We also conclude that at the low doses of most human exposures the comparative hazards of synthetic pesticide residues are insignificant.

Animals↗
PubMed1990

Nature's chemicals and synthetic chemicals: comparative toxicology.

The toxicology of synthetic chemicals is compared to that of natural chemicals, which represent the vast bulk of the chemicals to which humans are exposed. It is argued that animals have a broad array of inducible general defenses to combat the changing array of toxic chemicals in plant food (nature's pesticides) and that these defenses are effective against both natural and synthetic toxins. Synthetic toxins such as dioxin are compared to natural chemicals, such as indole carbinol (in broccoli) and ethanol. Trade-offs between synthetic and natural pesticides are discussed. The finding that in high-dose tests, a high proportion of both natural and synthetic chemicals are carcinogens, mutagens, teratogens, and clastogens (30-50% for each group) undermines current regulatory efforts to protect public health from synthetic chemicals based on these tests.

Animals↗
PubMed1990

Cytogenetic damage induced by folate deficiency in mice is enhanced by caffeine.

Folate deficiency in Swiss mice increased the incidence of micronuclei in peripheral blood erythrocytes, indicating increased chromosomal damage in nucleated erythrocyte precursors. Caffeine enhanced the incidence of micronuclei in blood and bone marrow by up to 5-fold in folate-deficient mice at doses that did not significantly alter the micronucleus frequency in the presence of adequate dietary folate. The lower dose of caffeine used in this study (75 mg/kg) approaches doses received by humans who consume large amounts of caffeinated beverages. Since folate deficiency and caffeine consumption are highly prevalent in the human population, the potential for a similar interaction in man should be evaluated.

Animals↗
PubMed1990

Third chronological supplement to the carcinogenic potency database: standardized results of animal bioassays published through December 1986 and by the National Toxicology Program through June 1987.

This paper is the third chronological supplement to the Carcinogenic Potency Database that first appeared in this journal in 1984. We report here results of carcinogenesis bioassays published in the general literature between January 1985 and December 1986, and in Technical Reports of the National Toxicology Program between June 1986 and June 1987. This supplement includes results of 337 long-term, chronic experiments of 121 compounds, and reports the same information about each experiment in the same plot format as the earlier papers, e.g., the species and strain of animal, the route and duration of compound administration, dose level, and other aspects of experimental protocol, histopathology, and tumor incidence, TD50 (carcinogenic potency) and its statistical significance, dose response, opinion of the author about carcinogenicity, and literature citation. The reader needs to refer to the 1984 publication for a guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. The four plots of the database are to be used together as results published earlier are not repeated. In all, the four plots include results for approximately 4000 experiments on 1050 chemicals. Appendix 14 of this paper is an alphabetical index to all chemicals in the database and indicates which plot(s) each chemical appears in. A combined plot of all results from the four separate papers, that is ordered alphabetically by chemical, is available from the first author, in printed form or on computer tape or diskette.

Carcinogenicity Tests↗
PubMed1990

Natural chemicals, synthetic chemicals, risk assessment, and cancer.

The administration of chemicals at the maximum tolerated dose (MTD) in standard animal cancer tests is postulated to increase cell division (mitogenesis), which in turn increases rates of mutagenesis and thus carcinogenesis. The animal data are consistent with this mechanism, because a high proportion--about half--of all chemicals tested (whether natural or synthetic) are indeed rodent carcinogens. We conclude that at the low doses of most human exposures, where cell killing does not occur, the hazards to humans of rodent carcinogens may be much lower than is commonly assumed. The toxicological significance of exposures to synthetic chemicals is examined in the context of exposures to naturally occurring chemicals. We calculate that 99.99% (by weight) of the pesticides in the American diet are chemicals that plants produce to defend themselves. Only 52 natural pesticides have been tested in high-dose animal cancer tests, and about half (27) are rodent carcinogens; these 27 are shown to be present in many common foods. We conclude that natural and synthetic chemicals are equally likely to be positive in animal cancer tests. The toxicology of synthetic chemicals is compared to that of natural chemicals, which represent the vast bulk of the chemicals to which humans are exposed. It is argued that animals have a broad array of inducible general defenses to combat the changing array of toxic chemicals in plant food (nature's pesticides) and that these defenses are effective against both natural and synthetic toxins. Synthetic toxins such as dioxin are compared to natural chemicals, such as indole carbinol (in broccoli) and ethanol. The finding that in high-dose tests, a high proportion of both natural and synthetic chemicals are carcinogens, mutagens, teratogens, and clastogens (30-50% for each group) undermines current regulatory effects based on these tests to protect public health from low doses of synthetic chemicals.

Antioxidants↗
PubMed1990

Oxidative stress and abnormal cholesterol metabolism in patients with adult respiratory distress syndrome.

Oxidative stress has been implicated in the adult respiratory distress syndrome (ARDS). In this study, we determined the levels of selected antioxidants in the plasma of 25 patients with ongoing ARDS and 16 healthy control subjects. We also examined these plasmas and pulmonary edema fluid of ARDS patients for lipid hydroperoxides. Both ascorbate and ubiquinol-10 concentrations in ARDS plasma were significantly lower than in normal plasma. alpha-Tocopherol concentrations, when standardized to total plasma cholesterol, were not lower in ARDS patients than in normal subjects. A pattern of antioxidant levels virtually identical to that observed in ARDS plasma was obtained after in vitro incubation of healthy plasma with stimulated polymorphonuclear leukocytes: very low ascorbate, decreased ubiquinol-10, and unchanged alpha-tocopherol concentrations. Nanomolar concentrations of lipid hydroperoxides were found in pulmonary edema fluid of ARDS patients, but not in plasma, nor in the plasma of healthy individuals, when a sensitive and selective chemiluminescence assay for hydroperoxides was used. ARDS patients also showed significant decreases in plasma levels of cholesterol esters in conjunction with discoidal high-density lipoprotein profiles, indicating a decrease in lecithin-cholesterol acyltransferase activity. We conclude that ARDS is associated with oxidative stress, possibly exerted by oxidants released from activated phagocytic leukocytes, and major changes in plasma cholesterol metabolism.

Adult↗
PubMed1989

Identification and molecular analysis of oxyR-regulated promoters important for the bacterial adaptation to oxidative stress.

The oxyR-encoded regulatory protein, OxyR, acts to induce the synthesis of a family of hydrogen peroxide-inducible proteins in Salmonella typhimurium and Escherichia coli. To further define the mechanism by which oxyR regulates the production of these proteins, we identified, mapped, and characterized oxyR-regulated promoters upstream from the S. typhimurium ahp genes (encoding an alkyl hydroperoxide reductase) and the E. coli katG gene (encoding catalase). A set of ahpC promoter deletions was constructed in vitro and analysis of these deletions revealed the location of sequences that are involved in oxyR-mediated induction of the ahpC gene product. DNase I protection studies of the ahpC promoter region revealed an oxyR-dependent footprint that overlapped the sequences found to be important for oxyR control. E. coli strains containing transcriptional fusions between the katG promoter and the lacZ gene showed strongly increased synthesis of beta-galactosidase in response to hydrogen peroxide treatment. This stimulation was found to be oxyR-dependent. DNase I protection studies of the katG promoter region revealed an oxyR-dependent footprint in the same location relative to the basal promoter elements as was observed with the ahpC promoter. Although both the ahpC and katG promoters were shown to bind the same factor, no strong sequence similarities were found between the two, or between the two and a third oxyR-dependent binding site upstream from the E. coli oxyR gene itself.

Bacterial Proteins↗
PubMed1989

Immunochemical identification of a tRNA-independent cytokinin-like compound in Salmonella typhimurium.

Chemical and immunological characterization of Salmonella typhimurium cell extracts indicates that this organism produces a molecule which closely resembles the plant growth regulator, cytokinin. Alcohol-soluble cationic ultraviolet-absorbing material was fractionated by reverse-phase HPLC using gradient conditions optimized previously for modified nucleoside separation. A single hydrophobic compound was identified in the cytokinin region of the gradient, and limited quantities of the compound were prepared by HPLC fractionation of crude extracts. The compound demonstrated significant activity in a radioimmunoassay for cytokinins which detects N6-isopentenylated adenine derivatives. Boronate affinity chromatography indicated the compound is likely to be ribosylated and therefore a nucleoside. These and other tests indicate the compound has the most notable structural characteristics of a cytokinin. Spectral analysis and chromatographic comparison with cytokinin standards indicate the compound also has some unique structural features. Presence of the compound in extracts of an S. typhimurium mutant blocked for synthesis of tRNA-derived cytokinins excluded tRNA as a source for the compound and implicates existence of a tRNA-independent pathway for cytokinin biosynthesis in this bacterial species.

Chromatography, Affinity↗
PubMed1989

An alkyl hydroperoxide reductase from Salmonella typhimurium involved in the defense of DNA against oxidative damage. Purification and properties.

A peroxide reductase (peroxidase) which converts lipid hydroperoxides and other alkyl hydroperoxides to the corresponding alcohols, using either NADH or NADPH as the reducing agent, has been identified in both Salmonella typhimurium and Escherichia coli. This enzyme is shown to play a role in protecting against alkyl hydroperoxide mutagenesis. To our knowledge this work represents the first description of an NAD(P)H peroxidase in enteric bacteria and the first reported bacterial peroxidase to exhibit high activity toward alkyl hydroperoxides. A high performance liquid chromatography-based assay for the alkyl hydroperoxide reductase has been developed by monitoring the reduction of cumene hydroperoxide, a model alkyl hydroperoxide. By using this assay, the enzyme has been purified from a S. typhimurium regulatory mutant, oxyR1, which overexpresses a number of proteins involved in defenses against oxidative damage, and which contains 20-fold more of the alkyl hydroperoxide reductase than the wild-type strain. The purified activity requires the presence of two separable components having subunit molecular weights of 22,000 and 57,000. The 57-kDa protein contains a bound FAD cofactor and can use either NADH or NADPH as an electron donor for the direct reduction of redox dyes, or of alkyl hydroperoxides when combined with the 22-kDa protein. This enzyme may thus serve as a prokaryotic equivalent to the glutathione reductase/glutathione peroxidase system in eukaryotes.

Benzene Derivatives↗
PubMed1989

Mutagenesis and carcinogenesis: endogenous and exogenous factors.

The understanding of mutagenesis and its relation to carcinogenesis and aging is developing rapidly. A number of new findings are relevant to our understanding and are discussed: 1) The endogenous rate of oxidative DNA damage is estimated to be 10(4) hits/cell/day in humans and an order of magnitude higher in rodents. 2) The induction of cell proliferation may be a critical factor in both human cancer and the cancer caused by the maximum tolerated dose (MTD) of chemicals in rodents. 3) About half of all chemicals tested, whether synthetic or natural, are carcinogens, including the group of nature's pesticides, the main (greater than 99%) toxic chemicals in our diet. It is not clear how much, if any, of this high percentage of carcinogens is due to bias in selection of chemicals. A reasonable explanation for a very high percentage of all chemicals being carcinogenic at the MTD is that the MTD causes cell proliferation and inflammation, risk factors for cancer. 4) In the evolutionary war between plants and animals, animals have developed layers of general defenses, almost all inducible, against a world of natural toxic chemicals. This means we are well buffered against toxicity at low doses from both man-made and natural chemicals. Thus, low doses of carcinogens appear to be both much more common and less hazardous than is generally thought.

Animals↗
PubMed1989

Endogenous DNA damage as related to cancer and aging.

The endogenous background level of oxidant-induced DNA damage in vivo has been assayed by measuring 8-hydroxydeoxyguanosine (oh8dG), thymine glycol and thymidine glycol in urine and oh8dG in DNA. The level of oxidative DNA damage as measured by oh8dG in normal rat liver is shown to be extensive (1/130,000 bases in nuclear DNA and 1/8000 bases in mitochondrial DNA), especially in mtDNA. The methylation adduct 7-methylguanine (m7G) has also been found. m7G is one of about 5 adducts found on methylating DNA, and oh8dG is one of about 20 adducts found on oxidizing DNA, e.g., by radiation. We also discuss 3 hitherto unrecognized antioxidants in man.

Aging↗
PubMed1989

OxyR, a positive regulator of hydrogen peroxide-inducible genes in Escherichia coli and Salmonella typhimurium, is homologous to a family of bacterial regulatory proteins.

The oxyR gene is required for the induction of a regulon of hydrogen peroxide-inducible genes in Escherichia coli and Salmonella typhimurium. The E. coli oxyR gene has been cloned and sequenced, revealing an open reading frame (305 amino acids) that encodes a 34.4-kDa protein, which is produced in maxicells carrying the oxyR clone. The OxyR protein shows homology to a family of positive regulatory proteins including LysR in E. coli and NodD in Rhizobium. Like them, oxyR appears to be negatively autoregulated: an oxyR::lacZ gene fusion produced 5-fold higher levels of beta-galactosidase activity in oxyR null mutants compared to oxyR+ controls, and extracts from an OxyR-overproducing strain were able to protect regions (-27 to +21) of the oxyR promoter from DNase I digestion. DNA sequence analysis of the oxyR2 mutation, which causes overexpression of oxyR-regulated proteins in the absence of oxidative stress, showed that the oxyR2 phenotype is due to a missense mutation (C.G to T.A transition) that changes alanine to valine at amino acid position 234 of OxyR.

Amino Acid Sequence↗
PubMed1989

An apaH mutation causes AppppA to accumulate and affects motility and catabolite repression in Escherichia coli.

apaH- mutants lack the hydrolase responsible for degradation of AppppN dinucleotides in Escherichia coli and show a greater than or equal to 16-fold increase in AppppA under nonstress conditions. These mutants lack detectable activity of sigma F, a factor required for transcription of motility and chemotaxis genes. Expression of the flbB/flaI operon, thought to encode sigma F, is decreased in apaH- mutants, and there appears to be a general decrease in expression of genes regulated by cAMP-binding protein and cAMP as well.

Cell Movement↗
PubMed1989

Ascorbate is an outstanding antioxidant in human blood plasma.

We have shown recently that the temporal order of antioxidant consumption in human blood plasma exposed to a constant flux of aqueous peroxyl radicals is ascorbate = protein thiols greater than bilirubin greater than urate greater than alpha-tocopherol and that detectable lipid peroxidation starts only after ascorbate has been consumed completely. In this paper, we show that it is indeed ascorbate that completely protects plasma lipids against detectable peroxidative damage induced by aqueous peroxyl radicals and that ascorbate is the only plasma antioxidant that can do so. Plasma devoid of ascorbate, but no other endogenous antioxidant, is extremely vulnerable to oxidant stress and susceptible to peroxidative damage to lipids. The plasma proteins' thiols, although they become oxidized immediately upon exposure to aqueous peroxyl radicals, are inefficient radical scavengers and appear to be consumed mainly by autoxidation. Our data demonstrate that ascorbate is the most effective aqueous-phase antioxidant in human blood plasma and suggest that in humans ascorbate is a physiological antioxidant of major importance for protection against diseases and degenerative processes caused by oxidant stress.

Antioxidants↗
PubMed1989

Urinary 8-hydroxy-2'-deoxyguanosine as a biological marker of in vivo oxidative DNA damage.

DNA is subject to constant oxidative damage from endogenous oxidants. The oxidized DNA is continuously repaired and the oxidized bases are excreted in the urine. A simple routine analytical procedure is described for urinary 8-hydroxy-2'-deoxyguanosine, an oxidative DNA damage adduct, as an indicator of oxidative damage in humans and rodents. This adduct was purified from human urine and characterized. The described assay employs a series of solid-phase extraction steps that separate 8-hydroxy-2'-deoxyguanosine from other urinary constituents, followed by analysis by gradient reversed-phase HPLC coupled to a dual-electrode high-efficiency electrochemical detection system. Analysis of urine from three species by this method indicates that mice excrete approximately 3.3-fold more 8-hydroxy-2'-deoxyguanosine than humans (582 vs. 178 residues per cell per day), a result that supports the proposal that oxidative damage to DNA increases in proportion to species-specific basal metabolic rates.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1989

Detection of DNA adducts by high-performance liquid chromatography with electrochemical detection.

A method for the detection of rare adducts in DNA has been developed by combining the resolution of high-performance liquid chromatography with the specificity and sensitivity of electrochemical detection. Many adducts are electrochemically active, while the normal bases, except for guanine, are not. Enzymatic hydrolysis of DNA is used to obtain the deoxynucleosides for analysis, or where appropriate, acid hydrolysis or thermal depurination of DNA is used to free the adduct base for analysis. Various types of DNA damage have been induced by in vitro exposure of DNA to acrolein, dimethyl sulfate, sodium nitrite, ascorbate/Cu2+ and gamma-irradiation. Several adducts are detected at a level of one adduct in 10(5)-10(6) normal bases in micrograms of DNA. The method is also useful for measuring O6-methylguanine (O6MeGua) in DNA from rats treated with N-nitrosodimethylamine and 8-hydroxydeoxyguanosine (oh8dG), and O6-MeGua in DNA from bacteria treated with hydrogen peroxide and dimethyl sulfate. oh8dG, which appears to be the most suitable marker for measuring the steady-state level of oxidative DNA damage, can be measured at fmol levels in DNA from normal rat tissues. The method is applicable to the analysis of DNA base damage caused by major endogenous processes relevant to aging, such as deamination, methylation and oxidation. The analysis of DNA adducts with this simple assay also may be potentially useful for studies on carcinogenesis and as a tool in studies on the epidemiology of cancer.

Animals↗