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M S Legator

Publications and source records attributed to M S Legator.

At least 109 records · Page 6Linked to original sources
PubMed1979

Bile as a source of mutagenic metabolites produced in vivo and detected by Salmonella typhimurium.

The in vivo metabolic activation of several mutagenic compounds was assayed in the bile of rats, with Salmonella typhimurium as the indicator organism. It was determined that for some compounds, particularly the aromatic amines, a substantial percentage of the compound was excreted into the bile as either a nonmutagenic glucuronide conjugate or a mutagenic metabolite of the compound. Relatively low doses of the chemical were detected, and it was possible to follow the excretion pattern of the compounds over the collection period.

Acetaminophen↗
PubMed1979

A combined testing protocol approach for mutagenicity testing.

The antischistosomal agent, hycanthone methanesulfonate (HMS), was employed to illustrate the utility of carrying out several mutagenicity tests in a single concurrent animal experiment. Several commonly used procedures that were successfully integrated into a multiple testing protocol included (1) metaphase analysis in bone marrow, (2) micronucleus test in bone marrow, (3) analysis of the urine for mutagenic constituents, and (4) the host-mediated assay using Salmonella typhimurium. In addition to these animal studies, in vitro mutagenicity testing with and without activation was carried out using S. typhimurium. HMS produced positive, dose--response effects in in vitro tests, metaphase analysis, micronucleus test, and urine analysis, but not in the host-mediated assay. The results of these integrated techniques suggest that such a protocol may be a benefit to those concerned with mutagenicity testing of chemicals.

Animals↗
PubMed1979

Chemical characterization of 465 known or suspected carcinogens and their correlation with mutagenic activity in the Salmonella typhimurium system.

Since chemicals exhibiting mutagenic activity pose a potential hazard to their users, there is increasing acceptance of mutagenicity testing as an integral part of a premarketing toxicological evaluation of chemicals. In vitro testing has gained much notoriety as quick and relatively inexpensive means to assess the mutagenic potential of chemicals. However, the innovative use of microsomes to simulate metabolism has not changed the fact that in vitro activation cannot duplicate faithfully the metabolism that occurs in vivo. This shortcoming will express itself by the production of false negatives and possibly false positives during mutagenicity screening. This assertion is also borne out by a reanalysis of the ability of known animal carcinogens to cause mutations in the generally recognized premier in vitro system, the Salmonella-S-9 system. Although previous studies have suggested that a high percentage (greater than 85%) of all carcinogens will be mutagenic in this system, with no indication that false negatives are associated with certain chemical types, these findings are of uncertain practical value due to the limited number of chemical types that were considered. An analysis of 465 compounds with known or suspected carcinogenic activity indicates that about 58% have been adequately tested in Salmonella, that the testing has concentrated on certain chemical types and has neglected others, and that some categories of carcinogens exhibit individual correlations that are unsatisfactorily low by any standard. Poorly detected categories of carcinogens include: azonaphthols; carbamyls and thiocarbamyls; phenyls; benzodioxoles; polychlorinated aromatics, cyclics, and aliphatics; steroids; antimetabolites; and symmetrical hydrazines. Nonstandard procedures are necessary to optimize the testing of chemicals that are bactericidal, that are volatile, or that cross-link DNA. False negatives appear to arise for two reasons: an inability to devise an in vitro activation system that can be reliably used in a standard way; and an inability to detect the entire spectrum of mutational events that can lead to the induction of cancer.

Antimetabolites↗
PubMed1978

Detection of alkylating agents by the analysis of amino acid residues in hemoglobin and urine. 1. The in vivo and in vitro effects of ethyl methanesulfonate, methyl methanesulfonate, hycanthone methanesulfonate, and naltrexone.

The effect of alkylating agents on the amino acid composition of rat and human hemoglobin has been examined. Because the amino acid compositions of these proteins are well established, the changes in the molar ratios of specific amino acids could be monitored in purified hemoglobin samples. Ratios of histidine, which is readily attacked by alkylating agents, to proline, which is not, were consistent in hemoglobin purified from untreated blood samples from 14 rats and 25 human subjects. Treatment of hemoglobin in vitro or in vivo with methyl methanesulfonate, ethyl methanesulfonate, or hycanthone methanesulfonate resulted in a loss of histidine residues relative to proline or phenylalanine. The decrease in histidine content increased with treatment dose and time and reached a maximum at about 15% of total histidine. Treatment of rats with methyl methanesulfonate or hycanthone methanesulfonate resulted in increased urinary excretion of methyl histidines.

Alkylating Agents↗
PubMed1977

A collaborative cytogenetics study to measure and minimize interlaboratory variation.

Six cytogenetics laboratories joined in a collaborative study of rat chromosome aberrations to measure interlaboratory variation in results of standardized procedures and to devise methods to minimize interlaboratory differences. A preliminary workshop was held to resolve scoring differences, to develop a joint protocol and common glossary, and to reach agreement on uniform reporting methods. Osborne-Mendel rats from a common source were sent to each laboratory. Triethylenemelamine (TEM) was used at doses of 100, 200, 300 and 400 microgram/kg to induce clastogenic effects; results were compared to those of a control group of untreated animals. Femoral bone marrow cells were evaluated with the scorers unaware of the dosage. Final results showed highly significant dose effects with the test compound, and most laboratories showed a similar pattern of dose response. This study illustrates that rat cytogenetic analysis can be an effective test system for evaluation of a compound for mutagenic potential, particularly for the index reflecting the proportion of abnormal cells, but that results should be interpreted cautiously when arbitrary values are assigned for some of the categories being analyzed, as was done in this project for the category of severely damaged cells.

Animals↗
PubMed1977

The contribution of metronidazole and two metabolites to the mutagenic activity detected in urine of treated humans and mice.

The urine of two patients receiving therapeutic doses of the trichomonacide, metronidazole, was analyzed for mutagenic activity using the histidine auxotroph TA1535 of Salmonella typhimurium. The activity detected in the urine was significantly higher than could be accounted for by the presence of the administered drug. Chromatographic analysis of the urine indicated the presence of the metabolite 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole, which when tested in vitro with TA1535 was found to be ten times more active than metronidazole. An additional urinary metabolite, 1-acetic acid-2-methyl-5-nitroimadazole, was found to be inactive when similarly tested. The in vitro mutagenic activity of metronidazole and the two metabolites was unchanged by the addition of phenobarbital- or Aroclor-induced rat liver homogenate to the test system. In addition, metronidazole and the hydroxymethyl metabolite reverted S. typhimurium TA100 but not TA1537, TA1538, or TA98, and the acetic acid metabolite failed to revert any of the tester strains. In studies with mice, metronidazole was required in excess of the human dose in order for significant amounts of the hydroxymethyl metabolite to be detected in the urine. Urine from mice pretreated with the hepatotoxin, carbon tetrachloride, prior to the administration of metronidazole demonstrated approximately a 50% reduction in mutagenic activity, and the formation of the urinary metabolites was inhibited. These findings indicate the production of metabolites from the parent compound by the liver of the intact animal which could not be determined by use of the standard in vitro liver homogenate system.

Animals↗
PubMed1976

Protocols for the dominant lethal test, host-mediated assay, and in vivo cytogenetic test used in the food and drug administration's review of substances in the gras (generally recognized as safe) list.

Protocols are described for the dominant lethal and in vivo cytogenetics test in rats and the host-mediated assay, using Salmonella typhimurium and Saccharomyces cerevisiae in mice, as used by the Food and Drug Administration in its mutagenicity review of substances from the generally recognized as safe (GRAS) list. In addition proctolols are described for in vitro mutagenicity tests with S. typhimurium and S. cerevisiae and for statistical treatment for evaluation of data from dominant lethal tests.

Animals↗
PubMed1975

Detection of mutagenic activity of metronidazole and niridazole in body fluids of humans and mice.

After humans were treated at therapeutic doses with the trichomonacide metronidazole (Flagyl) and the antischistosomal agent niridazole mutagenic activity was demonstrable in their urines when tested with the histidine auxotroph of Salmonella typhimurium. Both compounds were active in the host-mediated assay in mice, and evidence of activity was found in the blood and urine of mice treated with niridazole but not with metronidazole.

Animals↗
PubMed1975

An evaluation of the micronuclei test using triethylenemelamine, trimethylphosphate, hycanthone and niridazole.

To determine the feasibility of the micronuclei procedure for cytogenetic studies, a comparatively weak chromosome breaking agent, trimethylphosphate (TMP) and the potent alkylating agent, triethylenemelamine (TEM) were evaluated. The procedure followed was that of Matter and Schmid with the following modifications: (a) direct flushing of bone marrow with 0.2 ml calf fetal serum. (b) air drying slides for a period of only I h, and (c) the use of pH 6.0 phosphate buffer to dilute both Wright and Giemsa stains. With this technique a dose response curve was generated for both TMP and TEM, using mice as the experimental animal. With TMP, a doubling over background was found when a concentration of 0.5 g/kg per day for five days was administered. To establish a statistically significant doubling dose over the control, a minimum of five animals must be used with 2000 polychromatic cells being analyzed per animal. Of the two antischistosomal agents tested, hycanthone yielded an increase of 20-fold in the number of micronuclei over control at 40 mg/kg administered i.p. for five days, while with niridazole no increase in micronuclei at several concentrations tested both by single and multiple injection was found. The results obtained with these compounds compare favorably with what has been reported for the standard in vivo metaphase analysis.

Alkylating Agents↗