Friday, February 21, 2014

Side effects at the cellular level

The development of unintended consequences is one of the most significant events full of duplicity.   It leads to unplanned events that could unravel the whole experiment.  The cell knows it is not perfect and has prepared itself to a world of various stimulants that scientists around the world and nature keep creating.  The cell keeps its options open, ready to adapt.   Its flexibility to conversion expands its potential to undergo unplanned events or side effects.  Some of the side effects are favorable, other neutral, but still some have deleterious effects.

1. One such example are Reuptake inhibitors:
Whether it is a serotonin or Dopamine, inhibitor or reuptake, it results in increased extracellular concentrations of the targeted compound.  Now it is always of use to remind ourselves that not all compounds are target specific and that certain compounds can stimulate several receptors, therefore raising the possibility of creating unintended consequences that we can call "side effects".

2.Co-stimulation of several Receptors Versus Co-binding of several Receptors.
Multikinases have the advantage of blocking several of their targets, and may shutdown or activate several pathways.  Generally, this is a positive thing.   Side effects come along when some receptors blocked in the process lead to obligatory vital pathways or processes that are also shutdown or impacted, leading to miserable consequences.  One of the things most researchers fear is the distant presence of an unplanned receptor in the Brain!   You give a medication planned to act on a Muscle or a white cell, and you get a significant seizure side effect (real case).
Some Multikinases are so effective that they shut down the effect of other therapeutic interventions (don't try anti-VEGF and M-TOR inhibitor concurrently until you are sure of your purpose).

3.Adaptor genes:
The cell is a master of giving directions to cellular reactions.  To achieve this it put stogether "Core Binding Factors" (term used here loosely to make a point) or a congregate of various molecules that may come together to master, interact and shape sometimes one molecule (give this molecule a specific post-translational modification) into a new molecule that will achieve a specific a factory would! ie.  check the prognosis of CBF presence in Leukemias!
Certain genes, however, orient squarely a molecule to some clear purpose, if a molecule A attaches to  the LYN gene Vs Gerb2, consequences are drastically different....Whether a solid tumor or a hematologic disease results could be a matter of which Adaptor gene was used!

4. Co-binding of Receptor
5. Lack of Inhibitors
6. Non specificity, sing the common pathways and possibility of saturation
7. Secondary liberation and release of "second messenger"
8. Unique localization of certain common receptors
9. Susceptibilty of certain Heterogeneic genes
10. The G proteins
etc.; all these could be expanded to justify why side effects develop, like it or not, in cellular life...No wonder we have to give "consents" for clinical trials....
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