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In pharmacology, we studied the development of tolerance to the therapeutic effects of drugs. It is defined as the diminished response of the body to a drug as an adaptation to its continued presence.

However, the factors like enzymes and hormones (either autocrine, paracrine, or endocrine) are also continuously present throughout the body in a steady state concentration or fluctuating concentrations (depending on the function and homeostatic requirements). So why, and how, does the body not develop tolerance to its own enzymes and hormones?

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  • $\begingroup$ There's a false premise here. Sometimes we do develop a tolerance for our own enzymes, etc. Obviously, this is not healthy. $\endgroup$
    – user3970
    Commented Sep 18, 2023 at 16:32
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    $\begingroup$ I find your question unanswerable without your naming a specific example of a drug to which the body develops tolerance, and a specific example of a (preferably similar) molecule (what you call a "factor") that you think should invoke a similar tolerance but does not, explaining why think it should. The key to this, in my opinion, is the molecular mechanism for this "tolerance". I suspect you and others may be approaching this from the wrong angle and the question to ask yourself is why should another compound have such a mechanism, not why it lacks this. $\endgroup$
    – David
    Commented Sep 18, 2023 at 22:36

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Tolerance is just a special case of homeostasis. There definitely is some level of "tolerance" to endogenous substances: down-regulation or desensitization of receptors that are over-activated, negative feedback loops, etc, are ubiquitous in biology.

The mechanisms that manifest as tolerance to exogenous substances are often part of endogenous homeostatic pathways.

Commenter bob1 mentions insulin resistance as a classic case of "endogenous tolerance", and it's quite an important one as it results in type 2 diabetes.

For another example, the most common excitatory neurotransmitter in the brain is glutamate; too much glutamate release or excitatory responses that are too strong result in seizures. There are several pathways that you could consider contributing to "glutamate tolerance", including particular glutamate receptors that downregulate other glutamate receptors: when neurons are exposed to a lot of glutamate at once, they reduce their responsiveness to glutamate in the near future. Failures in this regulatory/tolerance pathway are one cause of epilepsy.

A third generalized example is that of receptor-mediated endocytosis, which can serve to import specific things into the cell when they bind with a receptor, but is also important in regulating the overall strength of signaling pathways. Whether a ligand is exogenous or endogenous, when binding a receptor causes internalization of that receptor there is one fewer receptor available to bind additional ligand.

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  • $\begingroup$ Bryan “…are often part of endogenous homeostatic pathways”. How many people will have a clue what this means? You work hard for this site. Give it a rest. $\endgroup$
    – David
    Commented Sep 17, 2023 at 18:55
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    $\begingroup$ The classic example would be insulin resistance. This leads to hyperinsulinemia and can result in type 2 diabetes if the resistance gets too high. $\endgroup$
    – bob1
    Commented Sep 18, 2023 at 1:24
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    $\begingroup$ @Peter-ReinstateMonica Here's an example of a paper about tolerance to endogenous opioids: link.springer.com/article/10.1186/s40360-017-0193-y They claim evidence that tolerance of NSAID pain relief is mediated through reduced sensitivity to endogenous opioids. So, it isn't that tolerance can't or doesn't occur with response to the endogenous signals. Just that, when everything is "working properly", the body is somewhere near a homeostatic equilibrium. You need to perturb it or find a case of dysfunction to notice the regulation happening. $\endgroup$
    – Bryan Krause ♦
    Commented Sep 18, 2023 at 14:31
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    $\begingroup$ @David This feels like an appropriately technical answer to a technical question on a technical site. I don't understand what rest you think Bryan is supposed to give. $\endgroup$
    – user3970
    Commented Sep 18, 2023 at 16:30
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    $\begingroup$ @David I don't know, I think the question is a bit naïve to a biology professional, yes, but also insightful for a biology student given how these things are often taught in a biology/pharmacology classroom: it's likely that the concept of tolerance was introduced, and examples given, but the connection was not made between tolerance and regulation within biological systems more broadly. OP noticed that something didn't quite sit right, and asked a question about this conflict in their understanding. $\endgroup$
    – Bryan Krause ♦
    Commented Sep 19, 2023 at 17:36
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@Brian Krause's answer is completely correct. I'm only going to simplify it.

Tolerance to drugs develops because the enzymatic pathways (which are already in existence in the body, i.e. "are... endogenous homeostatic pathways") responsible for its metabolism enabling its removal from the body are increased, either by increased rate of metabolism or increased production of the enzyme(s) responsible for the drug's metabolism, etc. One of the most widely known such enzymatic pathways is the Cytochrome P450 pathway. (These are not the only ways tolerance develop, just the easier ways to measure.)

Tolerance to drugs is more noticeable because most drugs are xenobiotic, i.e. substances foreign to the body (or "exogenous substances"), so we must ingest them to get the intended effect, and the effect is noticeable, so when tolerance starts to develop, the dosage must be changed. So it's easy to observe tolerance to drugs. However, substances produced by the body are regulated without our being aware of it, because we're not visibly or otherwise noticeably actively doing anything; our bodies are to constantly compensating for internal processes, e.g. regulating our blood pH, glucose levels, etc. In a healthy individual, this is normal homeostatis, e.g. through positive and negative feedback, up- or down-regulation of substances produces, etc.. You mentioned hormones; thyroxine is a good example. Thyroxine is needed by nearly every cell in the body. The pituitary gland monitors (and controls) blood levels of thyroxine through the production of thyroid stimulating hormone (TSH) Low levels of thyroxine stimulate the production of TSH, whereas high levels causes decreased TSH production. of We're just unaware of all the regulation our body does until it overwhelms our ability to maintain homeostasis and becomes a problem of some sort, e.g. hyper/hypothyroidism, T2D (type 2 diabetes.), etc.

Cytochrome P450 Structure, Function and Clinical Significance: A Review
Drug Metabolism
Physiology, Thyroid Stimulating Hormone

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    $\begingroup$ Thank you, this is a great companion answer. I think you stated the most important concept for OP to recognize when you write "the effect is noticeable, so when tolerance starts to develop, the dosage must be changed. So it's easy to observe tolerance to drugs". That seems to be the main difference with exogenous factors: they can be changed quickly and the effects observed. If you did the same with synthetic versions of endogenous factors you'd see the same behavior. The distinction is in the presentation of the factor rather than the response of the system. $\endgroup$
    – Bryan Krause ♦
    Commented Sep 18, 2023 at 14:35

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