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Inability of tributyltin-induced chloride/hydroxyl exchange to stimulate calcium transport in mitochondria isolated from flight muscle of the sheep blowfly Lucilia cuprina.

ABSTRACT: Tributyltin in the concentration range 1-4mum failed to stimulate Ca(2+) transport by Lucilia flight-muscle mitochondria in a medium containing KCl and respiratory substrate but devoid of P(i), despite its promotion of a rapid Cl(-)/OH(-) exchange. When 2mm-P(i) was present, concentrations of tributyltin greater than 1mum inhibited the initial rate of Ca(2+) transport and induced efflux of the ion from the mitochondria in Cl(-)- or NO(3) (-)-containing media. Lower concentrations had little effect. Oligomycin added at up to 10mug/mg of mitochondrial protein had no effect on Ca(2+) transport. By contrast, approx. 0.3mum-tributyltin completely inhibited respiration supported by alpha-glycerophosphate in either the presence or absence of added ADP. The data suggest that tributyltin can inhibit Ca(2+) transport in Lucilia flight-muscle mitochondria other than by facilitating a Cl(-)/OH(-) exchange or producing an oligomycin-like effect.

SUBMITTER: Bygrave FL

PROVIDER: S-EPMC1186016 | biostudies-other | 1978 Sep

REPOSITORIES: biostudies-other

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Histone deacetylase enzymes as drug targets for the control of the sheep blowfly, Lucilia cuprina.

Project description:The Australian sheep blowfly, Lucilia cuprina, is an ecto-parasite that causes significant economic losses in the sheep industry. Emerging resistance to insecticides used to protect sheep from this parasite is driving the search for new drugs that act via different mechanisms. Inhibitors of histone deacetylases (HDACs), enzymes essential for regulating eukaryotic gene transcription, are prospective new insecticides based on their capacity to kill human parasites. The blowfly genome was found here to contain five HDAC genes corresponding to human HDACs 1, 3, 4, 6 and 11. The catalytic domains of blowfly HDACs 1 and 3 have high sequence identity with corresponding human and other Dipteran insect HDACs (Musca domestica and Drosophila melanogaster). On the other hand, HDACs 4, 6 and 11 from the blowfly and the other Dipteran species showed up to 53% difference in catalytic domain amino acids from corresponding human sequences, suggesting the possibility of developing HDAC inhibitors specific for insects as desired for a commercial insecticide. Differences in transcription patterns for different blowfly HDACs through the life cycle, and between the sexes of adult flies, suggest different functions in regulating gene transcription within this organism and possibly different vulnerabilities. Data that supports HDACs as possible new insecticide targets is the finding that trichostatin A and suberoylanilide hydroxamic acid retarded growth of early instar blowfly larvae in vitro, and reduced the pupation rate. Trichostatin A was 8-fold less potent than the commercial insecticide cyromazine in inhibiting larval growth. Our results support further development of inhibitors of blowfly HDACs with selectivity over human and other mammalian HDACs as a new class of prospective insecticides for sheep blowfly.

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