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Biomedical subjects

B N Ames

Publications and source records attributed to B N Ames.

At least 73 records · Page 4Linked to original sources
PubMed1996

Smoking and low antioxidant levels increase oxidative damage to sperm DNA.

Our previous studies have shown that men with low ascorbate intake have markedly increased oxo8dG in the DNA of their sperm. Because cigarette smoke is high in oxidants and depletes plasma and tissue antioxidants, oxidative DNA damage in sperm and tocopherol and ascorbate levels in seminal plasma were determined in smokers and non-smokers. The level in sperm DNA of oxo8dG, an oxidative lesion of guanine, was 50% higher in smokers compared to nonsmokers (p = 0.005). The concentration of alpha-tocopherol in seminal plasma was decreased in smokers by 32% (p = 0.03). Smoking and low antioxidant levels increase oxidative damage to sperm DNA. We discuss the possibility that paternal smoking causes mutations in sperm that lead to cancer, birth defects, and genetic diseases in offspring.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1996

Induction of cytochrome P4501A1 by 2,3,7,8-tetrachlorodibenzo-p-dioxin or indolo(3,2-b)carbazole is associated with oxidative DNA damage.

Induction of cytochrome P4501A1 (CYP1A1) in the hepatoma Hepa1c1c7 cell line results in an elevation in the excretion rate of 8-oxoguanine (oxo8Gua), a biomarker of oxidative DNA damage and the major repair product of 8-oxo-2'-deoxyguanosine (oxo8dG) residues in DNA. Treatment of this cell line with 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD), a nonmetabolized environmental contaminant, and indolo(3,2-b)carbazole (ICZ), a metabolite of a natural pesticide found in cruciferous vegetables, is shown to both induce CYP1A1 activity and elevate the excretion rate of oxo8Gua; 7,8-benzoflavone (7,8-BF or alpha-naphthoflavone), an inhibitor of CYP1A1 activity and an antagonist of the aryl hydrocarbon (Ah) receptor, reduced the excretion rate of oxo8Gua. The essential role of Ah-receptor, which mediates the induction of CYP1A1, is shown by the inability of TCDD to induce CYP1A1 and to increase excretion of oxo8Gua in Ah receptor-defective c4 mutant cells. While there was a significant 7.0-fold increase over 2 days in the excretion rate of oxo8Gua into the growth medium of TCDD-treated Hepa1c1c7 cells compared to control, no significant increase was detected in the steady-state level of oxo8dG in the DNA presumably due to efficient DNA repair. Thus, the induction of CYP1A1 appears to lead to a leak of oxygen radicals and consequent oxidative DNA damage that could lead to mutation and cancer.

Animals↗
PubMed1996

N2-methyl-8-oxoguanine: a tRNA urinary metabolite--role of xanthine oxidase.

DNA damage produces a series of oxidation products including 8-oxo-2'-deoxyguanosine and 8-oxoguanine, whose urinary excretion have been used to estimate in vivo oxidative injury. A monoclonal antibody to 8-oxoguanine was used to measure these adducts in urine taken from ill infants. In the process of this investigation we observed a large chromatographic peak that did not correspond to any of the known 8-oxoguanine adducts. A combination of liquid chromatography with electrochemical detection and gas chromatography/mass spectrometry allowed isolation and identification of the previously undescribed oxidation product, N2-methyl-8-oxoguanine. The excretion of this compound is increased in ill and growing infants but is also found in the urine of adult rats and humans. Experiments with allopurinol, a xanthine oxidase inhibitor, show that in humans, N2-methyl-8-oxoguanine is formed from the tRNA modified base N2-methylguanine. This is in contrast to the nonmethylated bases, which are converted to 8-oxo derivatives as a result of oxidative damage to nucleic acids and do not appear to be substrates for xanthine oxidase.

Animals↗
PubMed1996

Antioxidant activity of diethyldithiocarbamate.

Diethyldithiocarbamate (DDC), a potent copper chelating agent, has long been used for the treatment of oxygen toxicity to the central nervous system, as an immunomodulator to treat cancer, and in HIV-infected patients. We evaluated the antioxidant properties of DDC, including its scavenging of reactive oxygen species, its reducing properties, its iron-chelating properties, and its protective effects on oxidant-induced damage to brain tissue, protein, human LDL, and DNA. It is found that DDC is a powerful reductant and antioxidant since it scavenges hypochlorous acid, hydroxyl radical and peroxynitrite; it chelates, then oxidizes ferrous ions; it blocks the generation of hydroxyl radicals and inhibits oxidative damage to deoxyribose, protein, DNA, and human LDL. These findings may provide an explanation for the apparent beneficial effects of DDC against oxidative stress-related diseases that have been observed in experimental and clinical studies.

Animals↗
PubMed1996

Immobilization stress causes oxidative damage to lipid, protein, and DNA in the brain of rats.

Immobilization stress of male Sprague-Dawley rats induces oxidative damage to lipid, protein, and DNA in the brain. Significant increases in lipid peroxidation were found in the cerebral cortex, cerebellum, hippocampus, and midbrain compared to the unstressed controls. Significant increases in levels of protein oxidation were also found in the cortex, hypothalamus, striatum, and medulla oblongata. Oxidative nuclear DNA damage increased after stress in all brain regions, although only the cerebral cortex showed a significant increase. Depletion of glutathione showed some stimulation to oxidative damage in the unstressed control and stressed animals. Further studies of the mitochondrial and cytosol fractions of cerebral cortex demonstrated that mitochondria showed a significantly greater increase in lipid peroxidation and protein oxidation than cytosol. Data from plasma and liver showed oxidative damage similar to that of the brain. These findings provide evidence to support the idea that stress produces oxidants, and that the oxidative damage in stress could contribute to the degenerative diseases of aging, including brain dysfunction.

Animals↗
PubMed1995

The causes and prevention of cancer.

Epidemiological evidence indicates that avoidance of smoking, increased consumption of fruits and vegetables, and control of infections will have a major effect on reducing rates of cancer. Other factors include avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. A substantial reduction in breast cancer is likely to require modification of sex hormone levels, and development of practical methods for doing so is a high research priority. Resolution of the potential protective roles of specific antioxidants and other constituents of fruits and vegetables deserves major attention. Mechanistic studies of carcinogenesis indicate an important role of endogenous oxidative damage to DNA that is balanced by elaborate defense and repair processes. Also key is the rate of cell division, which is influenced by hormones, growth, cytotoxicity, and inflammation, as this determines the probability of converting DNA lesions to mutations. These mechanisms may underlie many epidemiologic observations.

Animals↗
PubMed1995

Mitochondrial decay in aging.

Several mitochondrial functions decline with age. The contributing factors include, the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.

Aging↗
PubMed1995

Oxidative DNA damage and senescence of human diploid fibroblast cells.

Human diploid fibroblast cells cease growth in culture after a finite number of population doublings. To address the cause of growth cessation in senescent IMR-90 human fibroblast cells, we determined the level of oxidative DNA damage by using 8-oxoguanine excised from DNA and 8-oxo-2'-deoxyguanosine in DNA as markers. Senescent cells excise from DNA four times more 8-oxoguanine per day than do early-passage young cells. The steady-state level of 8-oxo-2'-deoxyguanosine in DNA is approximately 35% higher in senescent cells than in young cells. Measurement of protein carbonyls shows that senescent cells did not appear to have elevated protein oxidation. To reduce the level of oxidative damage, we cultured cells under a more physiological O2 concentration (3%) and compared the replicative life span to the cells cultured at the O2 concentration of air (20%). We found that cells grown under 3% O2 achieved 50% more population doublings during their lifetime. Such an extension of life span resulted from the delayed onset of senescence and elevation of growth rate and saturation density of cells at all passages. The spin-trapping agent alpha-phenyl-t-butyl nitrone (PBN), which can act as an antioxidant, also effectively delayed senescence and rejuvenated near senescent cells. The effect is dose-dependent and is most pronounced for cells at the stage just before entry into senescence. Our data support the hypothesis that oxidative DNA damage contributes to replicative cessation in human diploid fibroblast cells.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1995

DNA damage in folate deficiency.

Folate deficiency significantly increases uracil content and chromosome breaks (as measured by micronucleated cells) in human leukocyte DNA. Folate supplementation reduces both the uracil content of DNA and the frequency of micronucleated cells, indicating that uracil misincorporation may play a causative role in folate deficiency-induced chromosome breaks. A calculation is presented to explain how the levels of uracil found in DNA could cause chromosome breaks. Based on this calculation, the frequency of uracil repair events that might result in double-strand DNA breaks increases by 1752-fold. These results are consistent with clinical and epidemiological evidence linking folate deficiency to DNA damage and cancer.

DNA Damage↗
PubMed1995

Sixth plot of the carcinogenic potency database: results of animal bioassays published in the General Literature 1989 to 1990 and by the National Toxicology Program 1990 to 1993.

This paper presents two types of information from the Carcinogenic Potency Database (CPDB): (a) the sixth chronological plot of analyses of long-term carcinogenesis bioassays, and (b) an index to chemicals in all six plots, including a summary compendium of positivity and potency for each chemical (Appendix 14). The five earlier plots of the CPDB have appeared in this journal, beginning in 1984 (1-5). Including the plot in this paper, the CPDB reports results of 5002 experiments on 1230 chemicals. This paper includes bioassay results published in the general literature between January 1989 and December 1990, and in Technical Reports of the National Toxicology Program between January 1990 and June 1993. Analyses are included on 17 chemicals tested in nonhuman primates by the Laboratory of Chemical Pharmacology, National Cancer Institute. This plot presents results of 531 long-term, chronic experiments of 182 test compounds and includes the same information about each experiment in the same plot format as the earlier papers: the species and strain of test 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, author's opinion about carcinogenicity, and literature citation. We refer the reader to the 1984 publications (1,6,7) for a detailed 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 six plots of the CPDB are to be used together since results of individual experiments that were published earlier are not repeated. Appendix 14 is designed to facilitate access to results on all chemicals. References to the published papers that are the source of experimental data are reported in each of the published plots. For readers using the CPDB extensively, a combined plot is available of all results from the six separate plot papers, ordered alphabetically by chemical; the combined plot in printed form or on computer tape or diskette is available from the first author. A SAS database is also available.

Animals↗
PubMed1995

Understanding the causes of aging and cancer.

Cancer, a disease typical of old age, is in large part of degenerative origin. Several factors leading to the development of cancer and other degenerative diseases are discussed. The results of cancer tests in animals have been misinterpreted; they are mainly carried out by using synthetic chemicals, whereas most carcinogenic substances are natural chemicals. Animals have defense systems which prevent them from the carcinogenic effects of both natural and synthetic chemicals.

Aging↗
PubMed1994

Extensive oxidative DNA damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop hepatocellular carcinoma.

A transgenic mouse strain that expresses the hepatitis B virus (HBV) large envelope protein in the liver was used to determine the extent of oxidative DNA damage that occurs during chronic HBV infection. This mouse strain develops a chronic necroinflammatory liver disease that mimics the inflammation, cellular hyperplasia, and increased risk for cancer that is evident in human chronic active hepatitis. When perfused in situ with nitroblue tetrazolium, an indicator for superoxide formation, the liver of transgenic mice displayed intense formazan deposition in Kupffer cells, indicating oxygen radical production, and S-phase hepatocytes were commonly seen adjacent to the stained Kupffer cells. Similar changes were not observed in nontransgenic control livers. To determine whether these events were associated with oxidative DNA damage, genomic DNA from the livers of transgenic mice and nontransgenic controls was isolated and examined for 8-oxo-2'-deoxyguanosine, an oxidatively modified adduct of deoxyguanosine. Results showed a significant, sustained accumulation in steady-state 8-oxo-2'-deoxyguanosine that started early in life exclusively in the transgenic mice and increased progressively with advancing disease. The most pronounced increase occurred in livers exhibiting microscopic nodular hyperplasia, adenomas, and hepatocellular carcinoma. Thus, HBV transgenic mice with chronic active hepatitis display greatly increased hepatic oxidative DNA damage. Moreover, the DNA damage occurs in the presence of heightened hepatocellular proliferation, increasing the probability of fixation of the attendant genetic and chromosomal abnormalities and the development of hepatocellular carcinoma.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1994

Detection and classification of mutagens: a set of base-specific Salmonella tester strains.

A detection and classification system for mutagens has been developed that identifies the six possible base-pair substitution mutations. A set of six Salmonella typhimurium (TA7001 to TA7006) strains has been constructed, each of which carries a unique missense mutation in the histidine biosynthetic operon. In addition to the his mutation, these strains carry different auxiliary features that enhance the mutability of the target his mutation. These include the R factor pKM101, which has the SOS-inducible mucAB system; a deletion of the uvrB component of excision repair; and rfa mutations to increase the accessibility of bulky chemicals to the bacteria. Another set of strains (TA7041 to TA7046) contain a wild-type rfa gene. Reversion via the base substitution unique to each strain was verified by sequence analyses of > 800 revertants obtained from different types of mutagens. The strains have considerably lower spontaneous reversion frequencies and detect a variety of mutagens at a sensitivity comparable to the Salmonella tester strains TA100, TA102, and TA104. The low spontaneous frequency of reversion of a mixture of the six tester strains (approximately 10 revertants per plate) enables a single mutation assay with the mixture that is followed by classification of the type of mutation with the individual strains.

Genes, Bacterial↗