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Of Inhibitors and IC50 Values Options
 
Infundibulum
#1 Posted : 9/13/2013 9:59:37 PM

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It is frequently that topics of enzyme inhibitors are brought into discussion; after all, aren't we all more-or-less interested in modulating the action of enzymes that normally break down and neutralise psychedelic substances? Particular attention has been given to harmala alkaloids since they are inhibitors of monoamine oxidase enzymes which normally metabolise tryptamine psychedelics, and not for a bad reason; harmalas are potent inhibitors of MAO. However, harmalas are not the only class of molecules that inhibit MAO (or have MAOI action). There are many reports of molecules other than harmalas (particularly) from plant sources that exhibit MAOI inhibitors and I always find it fascinating to read posts presenting new potential MAOIs. I am equally fascinated with reports of phytochemicals that inhibit other enzymes, such as the CYPs, since CYPs also have the capacity to metabolise psychedelics.

However, we have to be particularly wary of publications that report MAO- or CYP- or whatever other enzyme inhibition of a given phytochemical. The reason being that the devil is always in the details. Reports of enzyme inhibition for a given (phyto)chemical also come with a measured value, namely IC50. In the simplest of the terms, IC50 represents the concentration of the chemical at inhibiting 50% of the enzymes in question. Another value that is often met when reporting enzyme inhibition is Ki, which is analogous to IC50.

So what does the IC50 value mean? The simplest answer is that the lower the IC50 value, the stronger the inhibitor - and that makes perfect sense; strong inhibitors are active at low concentrations (and thus have low IC50 values) and vice-versa. But how do the IC50 values practically translate to how inhibitors affect our enzymes?

To address the latter question, let's consider the example of harmine; harmine inhibits MAO-A with an IC50 of 2.5nM. Translated in weight per volume, harmine's IC50 is 0.53ug/L. Now, imagine a person of 70kg ingesting 200mg of harmine; these 200mg will be diluted in a volume of ~70 litres of liquid, or in other words the average concentration that of harmine in this person's body will be 200mg / 70L, or ~2.85mg/L . Granted, the assumption that a person of 70kg has a volume of 70litres and that harmine will be evenly distributed comes from classical pharmacology, is outdated and not quite correct, but it is powerful in its simplicity and it gives us a rough idea of what is happening , numerically speaking.

So, the person that ingested 200mg of harmine has an average harmine concentration of 2.8mg/L, in his body and the harmine concentration needed to inhibit 50% of MAO-A is 0.53ug/L...in other words he took ~5000-fold the amount needed to inhibit 50% of MAO-A. In practical terms, he took enough to ensure that MAO-A are sufficiently inhibited.

Now, how about MAO-B? Harmine inhibits MAO-B with an IC50 of 25uM, or 5.3mg/L. It follows logically that ingestion of 200mg, which brings an average harmine body concentration to 2.8mg/L will not have any appreciable effects on MAO-B inhibition. Similarly, it has been argued here that harmine is inhibitor of CYP2D6. But since the latter inhibition has a Ki of 36.48uM, or 7.73mg/L, administration of 200mg of harmine won't bring appreciable inhibition of CYP2D6. To inhibit CYP2D6 with harmine at rates comparable to MAO-A inhibition, one would had to eat at least 100g of harmine! Using similar thinking, we can also see why piperine with an IC50 of 20.9uM against MAO-A is not a strong enough inhibitor if eaten at less-than-gram doses.

Now.....no single value (such as IC50 in this case) gives a perfect representation of the whole picture. IC50 values are measured always in vitro and they are a good, but incomplete guide of what actually happens in our bodies. We are way more complex than plant extracts acting on purified enzymes under defined lab conditions. Imagine this; a very strong MAO inhibitor which is excreted and/or metabolised extremely fast from our bodies will not act as good as its IC50 value predicts. Or, an average-strength MAO inhibitor that happens to linger around for longer time or possibly sequester where MAOI action is required will perform better than its IC50 value predicts. Despite however the existence of the odd cases, IC50 values are always a good starting guide to understanding and appreciating enzyme inhibition. And regardless of the "crudeness" of IC50, these values are extremely important at predicting behaviour of many pharmaceuticals, hence scientists putting the extra effort at measuring and implementing IC50 values. So let's do the same in the Nexus and start reporting IC50 when available along with any literature that demonstrates enzyme inhibitions!

Kind Regards,
Infun


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Sabnock
#2 Posted : 9/14/2013 5:26:18 AM
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Thanks for the clarification Infundibulum Smile
 
endlessness
#3 Posted : 9/14/2013 12:37:39 PM

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Thank you very much for this, Inf!

I was also thinking lately of the importance of this, and mentioned to nen in the passiflora thread since there´s a lot of interest in flavonoids and other substances that might inhibit MAOs.

One question, aren´t all enzyme substrates somewhat inhibitors of the enzyme (maybe in very high IC50 values), considering they at least temporarily occupy the enzyme´s activity?
 
FlyingFaders
#4 Posted : 9/14/2013 1:24:54 PM
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Thanks for this Infun!!!
Much appreciated!
 
 
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