At the moment, I treat cells with a drug to test the effect of the drug for an expression profile of transcription factors. In low concentrations of the drug, the expression of the transcription factors increase. At high concentrations of the drug the expression of the transcription factors decrease again (sometimes to exact the same level as untreated cells). Can anyone advise me about this phenomenon? Should this be expected?
We have seen non-monotonic (or sometimes referred to as biphasic) dose responses with some chemicals. They may show a decrease at low doses followed by an increase at high doses, or vice versa. A few examples I've seen in the toxicology literature would be androgen receptor-mediated gene expression, adenosine receptors A1 vs. A2, and repair of background DNA damage by enzymatic activity induced by adducts formed by a xenobiotic. I've also seen it for some genes in my own analysis of dioxin-exposure, gene expression data.
Just do a literature search for nonmonotonic or biphasic dose response and you should get some good hits on publications addressing it.
We have seen non-monotonic (or sometimes referred to as biphasic) dose responses with some chemicals. They may show a decrease at low doses followed by an increase at high doses, or vice versa. A few examples I've seen in the toxicology literature would be androgen receptor-mediated gene expression, adenosine receptors A1 vs. A2, and repair of background DNA damage by enzymatic activity induced by adducts formed by a xenobiotic. I've also seen it for some genes in my own analysis of dioxin-exposure, gene expression data.
Just do a literature search for nonmonotonic or biphasic dose response and you should get some good hits on publications addressing it.
Hello Michael, hello Guillaume,
thanks for your answers, they are very helpfull for me! The hint biphasic dose response is perfect for my search of the literature.
Best,
Sven
This might be due to the hormesis effect, where low concentrations of drugs activate a number metabolic events (detoxification) resulting in a net increase in transcription. Cells are usually metabolically more active (also consume more oxygen) than control without the drug. Higher concentrations of the drug are usually detrimental for the cell and the overall metabolism is reduced due to drug activity, which might be causing lower expression of trancript. regulators in your case.
Is there a great change in ionic strenght? Depeptization can occurr at dehydrating values of ionic strenght! By dehydration the equilibrium between the taumers can be shifted away from the Zwitterion tautomer, to the canonical, uncharged and less reactive species. Obviously pH is also a factor that needs to be controlled!
The Zwitterion species of course is the species more reactive towards anionic and cationic chemicals and the combined saline-H-bonding links affect stability properties tremendously.
Hello David, interesting idea. Never think of control the pH, I will do this. Normally I think there is no different because I change media and then give the drug to the cells. The cultivation time then is only 24 hours and the media with pH indication have allways the same colour.
pH could account for the effect, but ionic strenght(salinity) has tremendous effects on the pKa values of protein side groups and even solubility characteristics in such a way that titration curves for amino-acids, peptides and proteins (even insoluble fibrous ones like leather). The titration curves actually "rotate" about the isoelectric point as salinity increases.Collagen's "peptization" increases to a maximum as shown by neutral salt swelling at isoelectric pH values, up to 5 Baumes and then deswells, the weight do to absorbed water then decreases and passes through zero and continues to decrease, passes through zero again and as further dehydration occurs and the zwitterion tautomer decreases and thus the solubility curve displays a parabolic character. This is commonly seen even in ordinary aminoacids present in water. The control of the tautomer ratio is the parameter tanners employ for controlling penetration, reaction and fixation of tannery chemicals to collagen. I hope this is clear, but feel free to ask for more details! Cooks that prepare salted fish, will rewet it in solutions maintained at 5 Baumes for this reason.
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