1. A mechanism for the removal of the 14alpha-methyl group in ergosterol biosynthesis that involves the intermediacy of an 8,14-diene system is outlined. 2. In accordance with the requirements of ...this scheme, it is shown that 5alpha-ergosta-8,14-dien-3beta-ol is converted into ergosterol by Saccharomyces cerevisiae.
Primary cell cultures derived from Chinese hamster lung (CHL) were established, and their response for the induction of sister-chromatid exchange (SCE) by direct- and indirect-acting mutagens was ...characterized. An increase in SCE frequency was induced in CHL cells by 3-methylcholanthrene (MCA), benzoapyrene (BaP), and 2-aminoanthracene (2AA). The SCE frequency increased slightly after exposure to cyclophosphamide, but did not respond to the hepatocarcinogen dimethylnitrosamine (DMN). A slight increase in SCE frequency by DMN was observed in the CHL system with use of Aroclor-1254-induced rat liver homogenate fraction (S9). This response to DMN in CHL cells was lower than that seen when CHO cells were the target in the presence of S9. At low (1) and high (20) passages, the CHL cells responded with a similar dose-related increase in SCE frequency to direct- (ethyl methanesulfonate, EMS) and indirect-(MCA) acting mutagens. This response indicates that even after prolonged culturing in vitro, the cells retained the ability to metabolically activate xenobiotic promutagens. The induction of SCE by MCA occurred at concentrations that also induced macromolecular binding. SCE induction was also examined in primary lung cell cultures from animals exposed by nose-only inhalation to MCA aerosol. A significant increase in SCE frequency above controls was observed in cells from animals after a single exposure to MCA. No detectable increase in SCE frequency was observed after repeated inhalation exposures. Because CHL cells are of lung origin and showed metabolic activity, the CHL system appears to be appropriate for study of the genotoxic potential of inhaled compounds.
Extracts of three complex organic environmental mixtures, two from an experimental coal gasifier (a raw gas and a clean gas sample) and one from a coke oven main, were examined for genotoxicity. ...Three short-term genotoxicity assay systems were used: Ames Salmonella typhimurium reverse mutation assay, Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl transferase (CHO/HGPRT) gene locus mutation assay, and the Chinese hamster lung primary culture/sister chromatid exchange (CHL/SCE) assay. Aroclor-1254-induced rat liver homogenate fraction (S-9) was required to observe genotoxicity in both gene locus mutation assays (CHO/HGPRT and Ames). The relative survival of CHO cells exposed to extracts was highest in cells exposed to clean gas samples, with the raw gas sample being the most cytotoxic either with or without the addition of S-9. All three complex mixtures induced sister chromatid exchanges in primary lung cell cultures without the addition of S-9. The relative genotoxicity ranking of the samples varied between the mammalian and prokaryotic assay systems. Coke oven main extract produced fewer revertants in bacteria than the raw gas sample. However, the coke oven main extract was more genotoxic in the two eukaryotic systems (CHL/SCE and CHO/HGPRT) than was the raw gas sample. The results of all three assays indicate that the cleanup process used in the experimental gasifier was effective in decreasing the genotoxic materials in the process stream. These data also reemphasize the necessity of evaluating genotoxicity of complex mixtures in a variety of short-term systems.
The mammalian acute and genetic toxicity of 1-nitropyrene (NP) was studied because this and other nitroarenes are highly mutagenic toward bacteria and have been identified in emissions from ...combustion processes. A suspension of NP did not cause observable signs of acute toxicity and was not lethal when administered to male and female rats at single oral doses as high as 5.0 g/kg. Histological examination of stomach, intestine, lung, heart, spleen, pancreas, adrenal, and kidney from rats euthanized at 4 and 14 d after treatment revealed no detectable differences from control rats. Urine and feces were collected for 4 d after treatment with 5.0 g/kg. About 70% of the dose was present in the feces as NP, and about 2% was present as the reduced metabolite Uaminopyrene (AP). Sulfate and glucuronide conjugates of AP were present in small amounts (<1%) in the urine, showing that at least some of the dose was absorbed. Bone marrow cells from female rats given NP orally at 0.5, 1.5, and 5.0 g/kg showed a slight dose-related increase in the frequency of sister chromatid exchanges. Both NP and AP showed low mutagenicity in Chinese hamster ovary cells in vitro. Evidence of reductive metabolism of NP in rats raises concern about the potential exposure of humans to this compound. However, the weak in vivo and in vitro genetic toxicity of NP at high dose levels in mammalian systems suggests that the potential hazard may not be as high as predicted from bacterial mutagenicity data.
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