How to increase / induce CYP3A4 activity?

[jason30]

Hi all,

After years of struggling with some supplements, I have found a similarity; they all inhibit or decrease CYP3A4.

23andme
I have CYP3A4*16 T185S +/+ (source 23andme). And this means already a decreased activity of this important enzyme! (source: https://www.ebmconsult.com/articles/genetic-polymorphisms-cytochrome-p450-cyp3a4-enzyme)

Sups
Astragalus: https://pubmed.ncbi.nlm.nih.gov/23876595/
Uva ursi: https://www.tandfonline.com/doi/full/10.1080/13880200600746196
Milk Thistle dcreases the Activity of CYP3A4 http://dmd.aspetjournals.org/content/28/11/1270
Schisandra fruit is a potent inhibitor of CYP3A4; https://www.ncbi.nlm.nih.gov/pubmed/15342469

After intake of one of these sups I react badly to toxins, this takes days and sometimes a week. And that may make sense in some way because Cytochrome P450 3A4 (abbreviated CYP3A4) is an important enzyme in the body which oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body.

So my assumption is that when I increase the enzyme activity I may have fewer reactions / problems after taking these supplements.

Does anybody have tips to increase / induce CYP3A4 activity?

Thanks in advance for thinking along.

 

[Wishful]

Interesting observation. I'm not familiar with that enzyme or liver issues, but I've got my own "Why are these things doing that?" questions, so I like stories where the someone actually finds something useful from their observations and hypotheses.

 

[YippeeKi YOW !!]

Does anybody have tips to increase / induce CYP3A4 activity?

This is a baffling head-scratcher, and I dont tink I have an answer, but I do have a few digits of info that might help you figure this out.

The function of the isoenzyme CYP3A4 (it also has some close cousins, 3A5, 3A7, and a few others, but they function in different ways and on different elements) is to metabolize and terminate/neutralize or eliminate toxic bile acids, certain steroids, and phytochemicals in foods and a large proportion of medications. In doing this, other things can either INDUCE its activity, or INHIBIT it .... grapefruit is an example of a simple everyday food that can profoundly affect any substrate of the CYP3A4 enzyme. It's a powerful inhibitor of intestinal CYP3A4, and it has been posited to interact with numerous medications that result in serious adverse effects ...

The liver and the small intestine have the highest 3A4 activity, tho the 3A4 in the small intestine doesn't have the same actions that hepatic 3A4 does ....

Either way both forms of 3A4 are composed of proteins, like all other enzymes.

I have absolutely no idea how to increase the number or activity of 3A4 isoenzymes, altho I have some info on the substrates that would be involved in either induction or inhibition.

Some of the activity or lack of it in the 3A4 enzyme could be be either inhibited or induced by genetics, and by SNPS inherited genetically.

The variability of 3A4 drug metabolism can be aggravated by a lot of factors, including changes in liver function, the flow of blood, or lack of it, within the liver, the hormones circulating in your body, nutritional factors, and the aforementioned drug-drug interactions, or drug-food in some cases.

This is a sort of endless loop question: what induces the activity, or increases the available amounts, of something whose actions can, themselves, be induced or inhibited by exogenous substrates?

Maybe you could rephrase your question in a more accessible way .... ie, for idiots like me ? I'm not quite sure what you mean, and I'm pretty sure you dont want to take steady doses of phenobarbitol (an inducer) to boost your isoenzyme activity, even if that would translate laterally to any other endogenous substance that wasnt necessarily a substrate, which I'm pretty sure it wouldn't ....

Now I'm even confusing myself ....

My brain has started stuttering and tying itself in knots ....

I'd see myself out, but I cant seem to find the door ....

 

[Hip]

St John's Wort is an inducer of CYP3A4.




And grapefruit juice is a well-known potent CYP3A4 inhibitor. People taking medications which are metabolized by CYP3A4 have to be careful with grapefruit juice, as this juice increases blood levels of the medication.

 

[jason30]

Interesting observation. I'm not familiar with that enzyme or liver issues, but I've got my own "Why are these things doing that?" questions, so I like stories where the someone actually finds something useful from their observations and hypotheses.

There is still a lot we don't know, we need to do it with the information that is available. And it's hard to draw conclusions on things like this, because there are so many processes that underlie here.
But I have satisfaction when I experience fewer symptoms after increase/induce the activity of CYP3A4.

 

[jason30]

St John's Wort is an inducer of CYP3A4.

And grapefruit juice is a well-known potent CYP3A4 inhibitor. People taking medications which are metabolized by CYP3A4 have to be careful with grapefruit juice, as this juice increases blood levels of the medication.

That's a great tip Hip! Never knew that, I am definately gonna try St John's wort. Thanks a lot!

Yes, graprefruit juice gives me the same problems. Also Cat's Claw. That's also a reason why I believe the CYP3A4 plays a major role in my huge response to toxins.

Thanks again.

 

[jason30]

This is a baffling head-scratcher, and I dont tink I have an answer, but I do have a few digits of info that might help you figure this out.

The function of the isoenzyme CYP3A4 (it also has some close cousins, 3A5, 3A7, and a few others, but they function in different ways and on different elements) is to metabolize and terminate/neutralize or eliminate toxic bile acids, certain steroids, and phytochemicals in foods and a large proportion of medications. In doing this, other things can either INDUCE its activity, or INHIBIT it .... grapefruit is an example of a simple everyday food that can profoundly affect any substrate of the CYP3A4 enzyme. It's a powerful inhibitor of intestinal CYP3A4, and it has been posited to interact with numerous medications that result in serious adverse effects ...

The liver and the small intestine have the highest 3A4 activity, tho the 3A4 in the small intestine doesn't have the same actions that hepatic 3A4 does ....

Either way both forms of 3A4 are composed of proteins, like all other enzymes.

I have absolutely no idea how to increase the number or activity of 3A4 isoenzymes, altho I have some info on the substrates that would be involved in either induction or inhibition.

Some of the activity or lack of it in the 3A4 enzyme could be be either inhibited or induced by genetics, and by SNPS inherited genetically.

The variability of 3A4 drug metabolism can be aggravated by a lot of factors, including changes in liver function, the flow of blood, or lack of it, within the liver, the hormones circulating in your body, nutritional factors, and the aforementioned drug-drug interactions, or drug-food in some cases.

This is a sort of endless loop question: what induces the activity, or increases the available amounts, of something whose actions can, themselves, be induced or inhibited by exogenous substrates?

Maybe you could rephrase your question in a more accessible way .... ie, for idiots like me ? I'm not quite sure what you mean, and I'm pretty sure you dont want to take steady doses of phenobarbitol (an inducer) to boost your isoenzyme activity, even if that would translate laterally to any other endogenous substance that wasnt necessarily a substrate, which I'm pretty sure it wouldn't ....

Now I'm even confusing myself ....

My brain has started stuttering and tying itself in knots ....

I'd see myself out, but I cant seem to find the door ....

haha well, you don't confuse me Thanks for thinking along and the extensive information, very interesting to read.

Do you by change know more about the genetics which induce the activity of the 3A4 enzyme?

It's very interesting to read that both forms of 3A4 are composed of proteins (like the other enzymes). Do you maybe have more information about this subject, researches? I'd love to read more about this.

Thanks again.

 

[YippeeKi YOW !!]

But I have satisfaction when I experience fewer symptoms after increase/induce the activity of CYP3A4.

How. exactly, do you create that induction / increase in the action of CYP3A4?

That's a great tip Hip! Never knew that

I postd that same info for you a few posts before Hips .... sigh .....

 

[YippeeKi YOW !!]

Do you by change know more about the genetics which induce the activity of the 3A4 enzyme?

Not off-hand, and am not in the kind of shape today the would permit a deep search of my enormous, unwieldy file re nutritional substances, herbs, and any other type of potential helper for this crappy little ice-floe of an illness....

It's very interesting to read that both forms of 3A4 are composed of proteins (like the other enzymes). Do you maybe have more information about this subject, researches? I'd love to read more about this.

Give it a quick Google .... I found a LOT of info at NIH and Hindawi, among others ...

 

[jason30]

How. exactly, do you create that induction / increase in the action of CYP3A4?

I postd that same info for you a few posts before Hips .... sigh .....

I was referring to St John's Wort as an inducer of CYP3A4. Never knew that.

 

[jason30]

Not off-hand, and am not in the kind of shape today the would permit a deep search of my enormous, unwieldy file re nutritional substances, herbs, and any other type of potential helper for this crappy little ice-floe of an illness....

Give it a quick Google .... I found a LOT of info at NIH and Hindawi, among others ...

Will do, thanks again.

 

[YippeeKi YOW !!]

I was referring to St John's Wort

Oooops ..... my bad ..... feeling a little insecure much ???

A good source of things that will either induce or inhibit 3A4, among other enzyme pathways, is the Flockhart table.

There's also a source from the US gov, but in a series of computer crashes over last 2 weeks, I've lost those tabs/links. Just google Flockhart tables. That should bring it up .....

 

[jason30]

Oooops ..... my bad ..... feeling a little insecure much ???

A good source of things that will either induce or inhibit 3A4, among other enzyme pathways, is the Flockhart table.

There's also a source from the US gov, but in a series of computer crashes over last 2 weeks, I've lost those tabs/links. Just google Flockhart tables. That should bring it up .....

hehe no problem

Yes the drug interaction table is very informative. I have seen it many times before but I forgot to check about 3a4, I see now that st johns wort is also listed as an inducer.

I have came across this line:
"CYP3A is responsible for the metabolism of endogenous steroids (e.g. testosterone) or activation of dietary mycotoxins (e.g. aflatoxin) which are potential carcinogenic factors. "
Source: CYP3A43 - an overview | ScienceDirect Topics

That sounds likes a bad thing? Activating mycotoxins which are potential carcinogenic factors is not something we want?

 

[YippeeKi YOW !!]

That sounds likes a bad thing? Activating mycotoxins which are potential carcinogenic factors is not something we want?

Hmmmmm .... interesting question. And yes, distressing.

Merits deeper digging, which I'm incapable of right now, but I;ve definitely put that on my 'git 'er done' list ....

I've always assumed that the metabolizing done thru the liver enzymes involved the REMOVAL of xenobiotics from the body thru oxidation, not sending them free public transport to assist in further and deeper invasion ....

Damn. Just damn .... I was sure I had that one right. Just .... damn.

 

[jason30]

Hmmmmm .... interesting question. And yes, distressing.

Merits deeper digging, which I'm incapable of right now, but I;ve definitely put that on my 'git 'er done' list ....

I've always assumed that the metabolizing done thru the liver enzymes involved the REMOVAL of xenobiotics from the body thru oxidation, not sending them free public transport to assist in further and deeper invasion ....

Damn. Just damn .... I was sure I had that one right. Just .... damn.

Same here, I am surprised!
I react badly to mold toxins (I can't stay in a house with a lot of mold) so this is quite interesting to know, but at the same time very confusing. Inhibit CYP3A4 is a bad thing in terms of metabolizing meds and toxins, but activating is a bad thing as well in terms of mold toxins. Argghhhhh

"Aflatoxin B(1) requires cytochrome P-450 (CYP)-mediated activation to form cytotoxic and DNA-reactive intermediates, and this activation in human liver is mediated by the CYP 1A2 and 3A4 isoforms. "

Aflatoxin B1 (AFB1) is the most toxic and widely distributed of all identified aflatoxins [3,4]. AFB1 is not toxic in its native form, but highly activated when converted to electrophilic AFB1 exo-8,9-epoxide (AFBO) in vivo [5,6]. AFBO is highly reactive and easily intercalates into DNA, resulting in the genotoxicity of AFB1 [7]. Extensive research has confirmed that CYP3A4 and CYP1A2 play central roles in the bioactivation of AFB1 in human [8,9,10], though there remain some controversies about their relative dominance during this process [10,11,12,13].
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037493/

Then this;

GST-catalysed conjugation of activated AFB1 is thought to be the most important detoxification system and to play a key role in the protection of tissues from AFB1 toxicity. Actually, both and classes of GST were able to conjugate AFB1-8,9 epoxide (Gopalan et al., 1992) as a function of animal species differences in microsomal activation resulting in different ratios of exo- and endo-epo-xides. In case of humans, Liu et al (1991) demonstrated that incubation of liver preparations from patients expressing high hepatic GSTM1 activity, inhibited the formation of AFB1-DNA adducts more than those from individuals with lower corresponding activity.

The toxicological significance of glucuronidation and sulfation would probably be minimal since the
carcinogenic potency of the parent AFB1 is 15 times that of AFM1 (Campbell and Hates, 1976).

So glutathione is again very important for people in a mold environment where Aflatoxins are in the air. Activation of GSTM1 (Glutathione S-Transferase Mu 1) leads to less problems with the alfatoxins.

Hepatic biotransformation increases the polarity of xenobiotics, thereby increasing their solubility in water and enhancing their biliary and renal excretion biotics. In relation to their hepatotoxicity, several studies demonstrate the inhibitory effects of the major mycotoxins on hepatic biotransformation enzymes.

Such results strengthen the hypothesis that the normal metabolism of xeno-biotics by the liver could be altered during chronic exposure to mycotoxins, particularly in humans or animals exposed to aflatoxin B1, T-2 toxin, déoxynivalénol, nivalenol or fumonisin B1.

So on the end most enzymes in phase 1 gets inhibited by the mold toxins.

 

[jason30]

GSTM1/GSTP1: these are hugely important in detoxifying metals, car and diesel exhaust, solvents, herbicides, pesticides and other chemicals. It is possible, with specific supplements, to improve function of this family of enzymes, making the liver better at its job.

This line shows where my biggest problems lie, for example when I am exposed to pesticides I end up in the hospital.
I am curious which specific supplements can improve GSTM1.

 

[YippeeKi YOW !!]

Choline bitartrate comes to mind, but am still kinda rocky so not sure I'm remembering right .... give it a googl and see what you find.

And it also depends on the kind of pesticides. I think choline is a response to organophosphates, but again, not sure ....

It's a bitch when even your detoxifying systems start making deals with the devil ..... bah and humbuggery ....

Thanks for the info, it was extremely interesting if somewhat depressing ....