The Role of CYP3A in Health and Disease, Klyushova, et al, 2022

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darrellpf

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https://www.mdpi.com/2227-9059/10/11/2686

Abstract: CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes
isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. CYP3A enzymes are indiscriminate toward
substrates and are unique in that these enzymes metabolize both endogenous compounds and
diverse xenobiotics (including drugs); almost the only common characteristic of these compounds
is lipophilicity and a relatively large molecular weight. CYP3A enzymes are widely expressed in
human organs and tissues, and consequences of these enzymes’ activities play a major role both in
normal regulation of physiological levels of endogenous compounds and in various pathological
conditions. This review addresses these aspects of regulation of CYP3A enzymes under physiological
conditions and their involvement in the initiation and progression of diseases.
 
CYP3A4

Here is a candidate that fits the “virus attack followed by long term inflammatory response".

CYP3A4 is the most abundant liver enzyme affecting a very wide class of drugs. During a viral attack, the levels of CYP3A4 are significantly downregulated. There is an interaction with the immune system which can keep CYP3A4 downregulated.

While CYP3A4 is downregulated approximately 50% of drugs are either ineffective, misdosed or have longer term toxic effects that build up over weeks. This corresponds to ME/CFS "low and slow” dosing strategy and also to the variability of results.

Asking "How do the long term symptoms of CYP3A4 inhibition compare to the symptoms of ME/CFS?" yields a very good match.

CYP3A4 is very connected to bile acids, which play an important immune role. It is also involved in fat metabolism.

Women have higher levels of CYP3A4, so would be more affected by its inhibition.

CYP3A4 is involved with type 2 diabetes and metabolic syndrome.

The measurement of CYP3A4 is difficult and rarely done.

If we think of CYP3A4 being part of the "enzyme“ biome then its removal drastically changes the body's responses.

The most notable words that might perk up a doctor's ears are " St. John's Wort” which induces CYP3A4 and grapefruit juice, which is an inhibitor. There are other drugs that make grapefruit look like a bit player, such as ritonavir.

Historically, ritonavir, as one of the most potent inhibitors, has been used as a "booster” for other HIV drugs by killing the enzyme which decreases the clearance of the concomitant drugs. Ritonavir was repurposed as a booster in Pavloxid. During that time, due to a different population (older, obese, multiple drugs) the cautions were expanded and the suggested use was 5 days. Currently the CYP3A4 connection has become important in cancer drug dosing.

In layman's terms, my narrative would be: “The body has a defense mechanism when it encounters toxins, particularly during oral ingestion. If there is a sickness, viral, particularly with the possibility of ingestion, the body moves to a "siege” state. It initially decreases the breakdown of (ingested) items by limiting CYP3A4. It increases diarrhea to move the unprocessed items through. It moves using stored fat (hopefully collected during less toxic times) and decreases the hunger response. It stops helping " feed” a host of toxins that have a glucose metabolism.

This mechanism works well to get out of situations where the (ingestion) environment is bad temporarily, but will continue as long as the body/mind (as in HPA axis) believes it is still dealing with toxins.
 
There has already been a lot of discussion about "sickness response", Dauer, etc. You've asked the pertinent question. Is there a feedback loop that keeps the body in a sickness state? What if the body becomes sensitized to the presence of a particular toxin? Gall bladder dysfunction is common in ME/CFS so there's a strong CYP3A4 linkage.

What strikes me is that CYP3A4 is highly active player in the game, but at the same time we don't measure it.

The simple research would be to measure the level of CYP3A4 in ME/CFS and long covid compared to the normal population.
 
Utsikt said:
Where’s the data on that? Are there any studies?
Click to expand...
The first one I found on a quick scan papers here was

Risks of digestive diseases in long COVID: evidence from a population-based cohort study, 2024, Yuying Ma et al

Because they are close, I tend to look at long covid studies.

My suggestion is simply that since there are enough interesting interactions there is a viable avenue of exploration. Measuring works. Comprehensively looking at long covid and me/CFS symptomology and asking how CPA3A4 might be involved is also valuable.
 
I can state it a more broad way.

Chronic inflammatory states can impact bile acid metabolism.

And generally I always consider the converse to have some truth.
 
darrellpf said:
The first one I found on a quick scan papers here was

Risks of digestive diseases in long COVID: evidence from a population-based cohort study, 2024, Yuying Ma et al
Click to expand...
Found the thread: https://www.s4me.info/threads/risks...ased-cohort-study-2024-yuying-ma-et-al.36845/
darrellpf said:
Because they are close, I tend to look at long covid studies.
Click to expand...
Very few of the patients that have LC also have ME/CFS.

I have nothing against exploring different avenues to see if they are plausible on paper, and to design studies to explore the most promising in depth.

I’m just prodding at the underlying assumptions in order to better understand.
darrellpf said:
Chronic inflammatory states can impact bile acid metabolism.
Click to expand...
How would you define chronic inflammation?

If you ask Jonathan Edwards who’s worked on inflammation for decades, he’ll say that there are no signs of inflammation in pwME/CFS.
 
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