Glucocorticoids (Corticosteroids), the leeches of the 20th and 21st centuries
As kids in the 40s and 50s, when our parents drove us into Philly for our yearly shopping for school clothes at Jacob Reed’s, we’d pass a pharmacy just off the Ben Franklin Bridge which advertised leeches. Trash filled the streets and my brother and I used to call it FilthyDelphia.
One evening in 1967 as we were finishing up on the ward at Pennsylvania Hospital in Philadelphia, another first year neurology resident and I were discussing our patients before signing out. Both of us had to use high doses of glucocorticoids (corticosteroids) for inflammatory neurologic disease that day, and we well knew their severe short (gastric bleeding, anxiety, diabetes thrown out of whack) and long term (weight gain, osteoporosis, psychosis, myopathy) side effects.
I said that I thought docs in fifty years would look back on us using corticosteroids for inflammation the way we looked back on colonial docs using cupping, bleeding and leeches (Actually, a year or two later in the Air Force, a combat surgeon told me that leeches were absolutely the best way to debride a contaminated wound).
Sadly, it’s almost 60 years later, and while we know corticosteroids suppress inflammation, we still don’t know exactly how they do it.
Which brings us to a recent paper [ Nature vol. 629 pp. 184 – 192 ’24 ] While a complete understanding requires a deep dive into cellular biochemistry and molecular biology, but there are at least three important lessons here which don’t require any of it.
The first is that just because you completely understand a major action of a biologic agent (in this case glucocorticoids) they may have unsuspected other actions. This is called moonlighting — https://luysii.wordpress.com/2021/01/11/moonlighting-molecules/
The second is the deep complexity underlying a given cellular effect.
The third is an explanation of some unwanted drug side effects
First lesson: We’ve known ‘exactly how’ glucocorticoids work for years. They are small molecules resembling cholesterol which bind to a large protein called the glucocorticoid receptor found in the nucleus. When this happens the glucocorticoid receptor binds to our DNA genome which has the effect of turning on anti-inflamatory genes found near where the receptor binds in DNA. Game, set and match.
However glucocorticoids also bind to another protein (pyruvate dehydrogenase) increasing its activity. This also has an anti-inflammatory effect which brings us to the
Second lesson: Complexity (here is where you may skip the deep dive).
l. Increased activity of the pyruvate dehydrogenase complex results in increased flux through the tricarboxylic acid cycle of mitochondria.
2. Increased flux through the tricarboxylic acid cycle of mitochondria results in production of an obscure metabolite called itaconic acid.
3 Itaconic acid increases the activity of several proteins (NRF2, ATF3) which are transcription factors for anti-inflammatory genes.
4. The activation effect may be to to alkylation of KEAP1 (KelchLike Ech Associated Protein 1) which stabilizes NRF2 and AFT3.
Third lesson: Some drug side effects might be due to the drug binding to another (and unsuspected) molecule producing something unwanted. For a few examples please see — https://luysii.wordpress.com/2013/05/29/why-drug-discovery-is-so-hard-reason-22b-drugs-arent-always-doing-the-things-we-think-they-are/