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Biomedical subjects

C S Aaron

Publications and source records attributed to C S Aaron.

At least 55 records · Page 3Linked to original sources
PubMed1989

The in vitro unscheduled DNA synthesis (UDS) assay in rat primary hepatocytes: evaluation of 24 drug candidates.

The in vitro unscheduled DNA synthesis assay (UDS) is part of the routine genetic toxicology screening at The Upjohn Company. The purpose of this paper is to report results for 24 drug candidates which were tested as coded compounds. These compounds are very diverse in chemical structure and represent classes of compounds selected because of biological activity in a variety of preliminary drug efficacy screens. None of the compounds reported here produced an increase in UDS, and therefore, the UDS results with these materials do not suggest potential for mutagenesis or carcinogenesis.

Animals↗
PubMed1989

The CHO/HPRT assay: evaluation of 19 drug candidates.

The CHO/HPRT assay is used as part of basic mutagenicity screening batteries at the Upjohn Company. The results of this and other assays provides a way of identifying compounds likely to cause mutations in mammalian systems and for which additional testing may be required. This report provides results of testing 19 drugs and drug candidates for mutational properties in the CHO/HPRT assay. The results of these studies were uniformly negative. The diversity of structures and the fact that these compounds have potent (non-mutational) biological activity suggests that separation of mutagenic properties from other beneficial properties is feasible. These compounds have also been evaluated in several other assays (Aaron et al., 1989a-d) and were negative for genotoxicity. Thus, the results of this study and other available data fails to suggest any genotoxic hazard from these materials.

Animals↗
PubMed1989

The in vitro unscheduled DNA synthesis (UDS) assay in rat primary hepatocytes: evaluation of 2-furoic acid and 7 drug candidates.

The in vitro unscheduled DNA synthesis assay (UDS) is part of the routine genetic toxicology screening at The Upjohn Company. The purpose of this paper is to report results for 8 compounds which were tested in the in-house genetic toxicology program. These compounds represent diverse chemical structure and most of them entered the screening program because they are biologically active in efficacy screens. All tests were carried out under Good Laboratory Practices Regulations of the U.S. Food and Drug Administration. None of the materials reported here produced an increase in UDS and therefore the UDS results with these compounds do not suggest potential for genotoxicity.

Animals↗
PubMed1989

The Salmonella mutagenicity test: evaluation of 29 drug candidates.

The Salmonella mutagenicity test (Ames assay) is part of the routine screening battery applied to all new drugs at The Upjohn Company. The purpose of this paper is to report results for 29 compounds. These compounds are very diverse in chemical structure and represent classes of compounds selected because of known biological activity and other reasons. None of the compounds reported here produced an increase in revertant colonies in the Salmonella strains employed (TA98, TA100, TA1535, TA1537 and TA1538) and therefore the Salmonella mutagenicity results with these materials do not suggest potential for mutagenesis or carcinogenesis.

Animals↗
PubMed1983

Molecular dosimetry of the chemical mutagen ethyl methanesulfonate. Quantitative comparison of the mutagenic potency in Neurospora crassa and Saccharomyces cerevisiae.

Extending previous work with E. coli and mammalian cells in culture, forward-mutation frequencies induced by ethyl methanesulfonate (EMS) were quantitatively compared in Neurospora crassa and Saccharomyces cerevisiae under standardized conditions. Concomitantly, the actual dose to DNA was measured by determining the amount of radioactivity bound to DNA after treatment with tritium-labeled EMS. After exposure to EMS (2.5-50 mM), alkylation levels in N. crassa and S. cerevisiae were similar to those previously determined in E. coli and cultured mammalian cells. Consistently, there was a slightly less than proportional increase of the DNA alkylation level with the exposure concentration of the mutagen. Forward mutagenesis induced in yeast and N. crassa showed exponential kinetics with exponents of 1.5 and 2.6, respectively. These results are similar to those previously reported with E. coli, which differed from the results with cultured mammalian cells, where a linear dose-effect relationship between exposure and genetic effect was observed. These differences may reflect differences in the fate of EMS-induced adducts by cellular DNA repair systems, but are not due to initial differences in DNA alkylation levels. The fate and persistence of specific DNA adducts potentially responsible for pre-mutagenic changes are under investigation.

Animals↗
PubMed1982

The genetics of a small autosomal region of Drosophila melanogaster, including the structural gene for alcohol dehydrogenase. V. Characterization of X-ray-induced Adh null mutations.

Of 31 X-ray-induced and 2 spontaneous Adh null mutations selected for resistance to pentenol (Aaron 1979), 21 are deletions, including Adh and one or more neighboring loci. By contrast, none of 13 EMS-induced Adhn mutations are deletions. On average, the size of these X-ray-induced deletions is shorter than that of 12 formaldehyde-induced Adhn deletions (O'Donnell, Mandell, Krauss and Sofer 1977). Both the X-ray- and formaldehyde-induced deletions show a nonrandom distribution of break points in region 34D to 35D of chromosome arm 2L. Some of the deletions display particular genetic properties associated with one of their end points.

Alcohol Oxidoreductases↗
PubMed1981

X-ray induced sex-chromosome loss, when ring-X chromosome males are irradiated and mated to females carrying mei-9, mei-41 or mei-218.

Radiation damage induced in the sperm nucleus is repaired after this nucleus has entered the oocyte. The yield of induced genetic damage is known to be dependent on maternal genotype and can also be modified by treatment of the females with metabolic inhibitors. The experiments reported here were designed to find out whether a more specific analysis of the interaction between male gamete and oocyte cytoplasm can be carried out using mutants that are known to affect repair processes. Males carrying ring-X chromosomes were exposed to X-ray doses up to 1000 R and mated to females homozygous for a repair-deficient mutant. The mutants used were mei-9a, mei-9L1, mei-41A10, and mei-41D5. In addition a yellow (y) X chromosome was used as a control and an attempt was made to obtain data using mei-21815, a mutant at a locus not thought to affect repair. With mei-9 mutants there is an enhancement of the spontaneous and induced rates of paternal sex-chromosome loss. The mei-41 mutants did not affect the rates of paternal sex-chromosome loss. Mei-218 females were difficult to work with because they gave very few progeny. From these data it can be argued that repair-deficient mutants will indeed be useful for an analysis of the fixation of radiation-induced genetic damage.

Animals↗
PubMed1980

Molecular dosimetry of the chemical mutagen ethyl methanesulfonate: quantitative comparison of mutation induction in Escherichia coli, V79 Chinese hamster cells and L5178Y mouse lymphoma cells, and some cytological results in vitro and in vivo.

Molecular dosimetry studies were carried out to measure the extent of binding of radio-labeled ethyl groups to the DNA of Escherichia coli, V79 Chinese hamster cells and L5178Y mouse lymphoma cells treated with ethyl methanesulfonate (EMS). The results show that (1) the amount of ethylation of the DNA is similar in these cells when treatment conditions are identical, (2) the relationship between dose to DNA (ethylations per nucleotide) versus exposure (mM applied concentration) is non-linear in the sense that less alkylation of the DNA is observed at the higher exposures than would be predicted on the basis of proportionality between dose to DNA and exposure, and (3) the non-linearity of the genetic response in the bacterial cells is not reflected in a non-linearity of the alkylation of the DNA in those cells. Quantitative comparison of the frequencies of gene mutations in the various systems shows that the mutation frequency per unit of DNA alkylation is heterogeneous among the mammalian cell systems and that the frequencies observed in the bacterial cells fall within the range observed with mammalian cells. Alkylation of the DNA in the bone marrow, testis and liver of Swiss random-bred mice was also measured. The results support the conclusion that the distribution of the compound to the various tissues is rapid and probably uniform. Quantitative assessment of the cytological data (micronuclei, sister-chromatid exchanges, etc.) on the basis of dose was not as useful because of the low efficiency of EMS for inducing cytologically observable damage.

Animals↗
PubMed1980

gamma-Ray induced mutational spectrum in the lacI gene of Escherichia coli: comparison of induced and spontaneous spectra at the molecular level.

The spectrum of mutations induced by ionizing radiation (gamma-rays) was determined in the lacI gene of E. coli. Base substitution was the principal type of mutational event following ionizing radiation. Both transitions and transversions were produced, and no strong specificity for a particular base pair was observed. The spectra of spontaneous and of ionizing-radiation-induced base-pair changes differed significantly at several locations within the lacI gene. The location of 3 of these differences corresponded to sites of spontaneous deamination "hot spots" from which we conclude that gamma-rays do not cause extensive deamination. The specific locus rate was calculated as 4.5 X 10(-10) mutations per rad per gene copy per cell, and the nucleotide substitution rate was 2.2 X 10(-12) per rad. The frameshift mutation, trpE997, was not reverted by gamma-rays.

Base Composition↗
PubMed1979

X-ray-induced mutations affecting the level of the enzyme alcohol dehydrogenase in Drosophila melanogaster: frequency and genetic analysis of null-enzyme mutants.

The frequency of X-ray-induced (null-enzyme) mutations at the alcohol dehydrogenase locus in Drosophila melanogaster was measured. The rate of recovery of chromosomes that fail to direct the synthesis of a functional Adh protein is 3 x 10(-8) per R for chromosomes that do not include large chromosome rearrangements. However, this analysis excludes a larger number of chromosomes that are "null-enzyme mutations" because thye are deleted for the region of the Adh locus. The dose of X-rays required to induce a frequency of non-deletion null-enzyme mutants equal to the spontaneous frequency is about 73 rad calculated from the data reported in this communication.

Alcohol Oxidoreductases↗
PubMed1978

Molecular dosimetry of the mutagen ethyl methanesulfonate in Drosophila melanogaster spermatozoa: linear relation of DNA alkylation per sperm cell (dose) to sex-linked recessive lethals.

The dosage-response curve for EMS was determined with dose measured as ethylations of DNA per sperm cell, and response measured as the relative frequency of sex-linked recessive lethals induced in sperm cells of Drosophila melanogaster. Dose can be converted to ethylations per nucleotide of DNA by dividing ethylations of DNA per sperm cell by 3 X 10(8) nucleotides per sperm cell. Adult males were exposed to equal amounts of either [3H]EMS for determining dose or nonlabeled EMS for determining mutational response. By feeding EMS for 24 h in a concentration of 25 mM, a high dose of 1.4 X 10(-2) ethylations per nucleotide was observed. With 1.4% of the nucleotides ethylated, 57% of the X-chromosomes were hemizygously viable; therefore, ethylation per se is not very efficient in inducing mutations. The relative frequency of mutations increased linearly with the dose from a dose of 2.1 X 10(-4) to 1.4 X 10(-2) ethylations per nucleotide. No threshold was apparent, and the statistical limits of the exponent, 1.0 +/- 0.1, excluded an exponent as high as 1.2. This linear relation suggests no change in mechanism of mutagenesis occurs from low to high dose in Drosophila. A nonlinear relation was found between exposure and dose; when exposure was increased by a factor of 250 (from 0.1 to 25 mM EMS in the feeding medium) dose was increased by a factor of only 68. By extrapolating down from our lowest dose of 2.1 X 10(-4) ethylations per nucleotide with an observed frequency of 0.55% +/- 0.08% sex-linked recessive lethals, we estimate the doubling dose for sex-linked recessive lethals to be 4 X 10(-5) ethylations per nucleotide.

Alkylating Agents↗
PubMedDate not supplied

Quantitative morphometric analysis of pulmonary deposition of aerosol particles inhaled via intratracheal nebulization, intratracheal instillation or nose-only inhalation in rats.

The effectiveness of three techniques to deliver a diazo dye suspension into the lungs of rats was compared. The intratracheal nebulization (ITN) technique delivered 10 microl of the suspension per 5-ml puff of air in 10 puffs as an aerosol. The intratracheal fast instillation (ITFI) technique delivered 100 microl of the suspension in a single 2-ml puff of air as droplets. The nose-only inhalation (NI) technique aerosolized the suspension at an analytical concentration that provided a calculated dose equivalent to 100 microl of the suspension in a 2-h inhalation period. Immediately after dosing, all the rats were killed by exsanguination. The trachea was tied and the lung was inflated in situ with air. After fixation, 5-microm thick slices were prepared from each lobe of the lung at a plane perpendicular to the axis of the lobar bronchus at levels proximal, medial and distal to the hilus. The numbers of bronchi, bronchioli and alveolar ducts within four ranges of diameters and the proportion of each selected area of lung tissue with and without dye particles were quantified using electronic imaging analyzers. The results indicated that ITN and ITFI dispersed the particles evenly throughout most of the airways and in patches in the alveoli. The NI technique dispersed the particles homogeneously throughout the airways and the alveoli in the lungs. The mean number-percentage and the mean area-percentage data revealed that the doses delivered by ITN and NI were approximately 60% and 10%, respectively, of the ITFI dose. Thus, the ITFI technique appeared to be most suitable for pulmonary absorption and disposition studies where dosage precision is of primary concern. The ITN technique would need further improvement to meet the requirements for dose precision and particle distribution. For both ITFI and ITN, particle size was apparently not a critical determinant for deposition. The NI technique is suitable for inhalation toxicity studies where the pattern and uniformity of particle deposition is the primary concern.

Absorption↗