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Biomedical subjects

D Wilkie

Publications and source records attributed to D Wilkie.

16 recordsLinked to original sources
PubMed1979

Toxic and mutagenic effects of carcinogens on the mitochondria of Saccharomyces cerevisiae.

Nineteen haploid yeast (Saccharomyces cerevisiae) strains were used to assess the relative growth inhibitory potencies on fermentable vs. non-fermentable media of a collection of carcinogenic and non-carcinogenic chemicals. The majority of carcinogens were distinctly more potent on the non-fermentable (glycerol) medium, where mitochrondrial function is required for growth, than on the fermentable medium, where it is not. The anti-mitochondrial selectivity indicated by these growth tests was much slighter for the non-carcinogens. Similarly most carcinogens induced the cytoplasmic petite mutation whereas the non-carcinogens did not. Five carcinogens which were tested impaired the development of cytochromes aa3 and b in glucose cultures. Six carcinogens, when tested, inhibited growth on three fermentable sugars, the utilisation of which requires mitochondrial function. Out of five carcinogens which were examined, four suppressed the surface-dependent phenomenon of fluocculence in a flocculating strain of yeast, at concentrations primarily affecting the mitochondrial system; the fifth had a similar but less pronounced effect.

Carcinogens↗
PubMed1979

Mitochondrial activity of 2,6-diaminopurine in Saccharomyces cerevisiae.

2,6-diaminpurine (DAP) selectively inhibited mitochondrial protein synthesis in yeast cells with concomitant failure of cells to grow in non-fermentable (yeast extract, glycerol) medium. The selectivity was pronounced in all strains tested (15) nearly all of which were able to grow in yeast extract, glucose medium containing 5 mg/ml DAP (maximum solubility) whereas growth was arrested in all strains at 250-500 microgram/ml DAP in the glycerol medium. The inhibition was reversed by further addition of adenine to the culture medium. RNA synthesis in rat liver mitochondria was depressed by DAP suggesting that the analogue affected RNA polymerase activity. There was no evidence of nuclear mutagenicity by DAP but resistance to the antibiotics chloramphenicol and oligomycin was induced by the drug. Genetic evidence, although limited, indicated that the resistance mutations were cytoplasmic. The mitochondrial petite mutation was also induced by DAP but only at comparatively high concentrations. The mutagenic effects were seen only in the glycerol medium.

2-Aminopurine↗
PubMed1977

Mitochondrial biogenesis: inhibitors of mitochondrial protein synthesis.

The effects of erythromycin, chloramphenicol, cycloheximide, pyrimethamine, chromate, cadmium, lead, nickel, 4-nitro-quinoline-1-oxide and thioacetamide on yeast and human cells were studied. Inhibition of the synthesis of mitochondrial proteins resulted in the loss of cytochromes as well as in morphological changes in the cellular membranes and mitotic arrest. The data are discussed.

4-Nitroquinoline-1-oxide↗
PubMed1975

Mitochondrial and cellular inhibition by the folate analogue pyrimethamine in Saccharomyces cerevisiae: reversal of cellular effects by TMP.

The inhibitory effect of pyrimethamine on the growth of TMP-permeable strains of Saccharomyces cerevisiae in a fermentable medium supplemented with adenine, glycine, methionine and pantothenate was substantially reduced by exogenous TMP. This compound also suppressed the drug's killing effect, and to some extent its ability to induce the mitochondrial petite mutation. In a non-fermentable medium, TMP failed to reduce growth inhibition, in line with our earlier finding that as well as blocking synthesis pyrimethamine prevents mitochondrial protein synthesis.

Cell Division↗
PubMed1975

Loss of cytochrome oxidase in Saccharomyces cerevisiae during inhibition of mitochondrial protein synthesis by erythromycin and chloramphenicol.

There is a major reduction in respiratory competence, and inhibitionof growth, several hours after the addition of erythromycin or chloramphenicol to Saccharomyces cerevisiae growing in medium containing a non-fermentable carbon source. Spectrographic evidence is presented for a loss of cytochrome oxidase as a consequence of the antibiotic treatment. This loss is prevented by cyanide or oligomycin. When glucose is added, however, the loss occurs irrespective of the presence of the respiratory inhibitors. Cycloheximide does not affect respiratory competence or cause loss of cytochrome oxidase, and it prevents the loss elicited by erythromycin if both compounds are added together. However, if cycloheximide is added some time after the addition of erythromycin, it fails to block the response to the latter drug. The results cannot be accounted for on the basis of the segregation of a finite number of mitochondria into an increasing number of progeny cells but, rather, suggest that the mitochondria are modified during growth in chloramphenicol or erythromycin.

Chloramphenicol↗
PubMed1975

Genetical and biochemical aspects of resistance to p-fluorophenylalanine in Saccharomyces cerevisiae.

Growth of haploid yeast strains was inhibited by the phenylalanine (PA) analogue DL-p-fluorophenylalanine (FPA) in yeast extract media containing 0-2 mg PA/ml. Most strains had a maximum FPA tolerance of about 0-25 mg/ml when glycerol was the carbon source and 0-5 mg/ml in in glucose medium. Spontaneous FPA-resistant mutants isolated on glucose medium showed little or no increase in FPA tolerance over that of the parent when metabolizing glycerol. Resistance was controlled by a different nuclear gene in each of four mutants analysed. In a proportion of the mutants the amount of FPA incorporated into cellular proteins in competition with PA was less than into the proteins of sensitive parental cells, whether glucose or glycerol was used as carbon source. This suggests that the mutational change allowed the cytoplasmic system to descriminate against the analogue without affecting its incorporation into mitochondrially-synthesized proteins. Although attempts to measure the latter were not made, the observed decrease in respiratory activity of cells grown in the presence of FPA suggests such incorporation. In other mutants showing resistance to FPA in glucose medium, the amount of FPA incorporated into cellular proteins varied with the carbon source, less analogue being incorporated in glucose medium than in glycerol medium.

Cytochromes↗
PubMed1975

Selective inhibition of growth by the proline analogue thiazolidine-4-carboxylic acid and its probable mode of action in Saccharomyces cerevisiae.

Cells of Saccharomyces cerevisiae showed differential growth inhibition when cultured on various carbon sources in the presence of the proline analogue thiazolidine-4-carboxylic acid (TZ). On 0.5% yeast extract, 2% glucose and TZ (10 mg/ml) medium, growth lags from 8 to 10 h were observed, after which cells recovered and growth proceeded normally. Growth was totally inhibited on a medium of 0.5% yeast extract, 3% ethanol, and 5 mg of TZ per ml. This inhibition was not due to the inability of cells to undergo aerobic respiration, since similar media containing glycerol instead of ethanol allowed growth. Proline added to the culture medium reversed the lag on glucose and TZ medium but did not promote recovery on ethanol and TZ medium. TZ was found to have two probable modes of action in yeast. It was a noncompetitive inhibitor of yeast alcohol dehydrogenase, and it was also found to be incorporated into cellular protein. Uptake studies using (14)C-labeled TZ showed that the recovery on glucose was correlated with the progressive exclusion of the analogue from cells.

Carboxylic Acids↗
PubMed1975

Effect of pyrimethamine on the morphology and ultrastructure of Saccharomyces cerevisiae.

Sub-lethal levels of the folate analogue, pyrimethamine, caused pronounced cell elongation in Saccharomyces cerevisiae strain B41 when grown in glycerol medium. The orientation of bud development was also altered. Electron microscopy of thin sections showed an increase in cell wall thickness, but apart from this and the overall cell shape, the ultrastructure of the cells was normal. The structural abnormalities are attributed to alterations in the plasmalemma caused by protein synthesis inhibition in the mitochondria.

Cell Wall↗