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Inhibiting CYP2E1 for health?

Answered on August 19, 2014
Created April 30, 2013 at 12:00 AM

CYP2E1 is an enzyme system involved in the biotransformation/metabolism of a number of chemicals. The toxicity of the painkiller acetaminophen occurs when CYP2E1 metabolizes the drug into a chemical called NAPQI (1). NAPQI is a reactive compound which is toxic to hepatocytes, leading to liver damage when glutathione is insufficient to detoxify it.

It's not just acetaminophen that seems to have its toxicity increased by metabolism via CYP2E1. Other examples include benzene (2,6), acetone (3), acrylamide (4), styrene (7), diethylnitrosamine (9), carbon tetrachloride, chloroform, endotoxin (5).

Mice lacking a CYP2E1 are also protected from insulin resistance on a crappy diet (8).

Finally, according to this paper "CYP2E1 genetic polymorphisms leading to enhanced CYP2E1 gene transcription have been associated with increased risk of development of malignant tumours, through increased biotransformation of procarcinogens".

So my two questions from all this are essentially:

1) Might trying to downregulate CYP2E1 via diet/lifestyle be a worthwhile focus?

2) If yes, how could one go about this? Nicotine and alcohol are the commonly cited inducers of CYP2E1 (11,12), so there's one reason to chill out on the smoking and drinking. Corn oil also seems to do the trick (15,16), in rodents at least.

As far as inhibitors, the evidence seems pretty sparse. Maybe green tea (13,14)? Anyone know of others?

Thanks!

Cb9a270955e2c277a02c4a4b5dad10b5

(10989)

on May 03, 2013
at 03:33 PM

Like, I really think there's a reason Jack Lalanne lived to be 96 and died of, respiratory failure? I think. Study after study is showing the importance of exercise in cancer, diabetes, CHD, ability to control or lower inflammation, even in oral health. It all fits together nicely with the mitochondrial theory of disease I posted a while ago. The biggest questions left IMO are which physical activities are best (lots of options from CT to Sprint 8, walking, gardening, yoga), how dangerous is sedentary behavior independent of exercise, how important is diet, and how do these things interact.

Cb9a270955e2c277a02c4a4b5dad10b5

(10989)

on May 03, 2013
at 03:26 PM

Lol, thanks mscott, I'm still working on it though, now I'm just trying to learn more about the metabolic syndrome, chronic inflammation and seeing if there's a possible way to tie that together with maybe mitochondrial function and degenerative chronic diseases. I'm really thinking that physical activity of some sorts is going to show to be the connecting mechanism between all these things, assuming an otherwise adequate diet (but not necessarily a perfect diet).

A2c38be4c54c91a15071f82f14cac0b3

(12682)

on May 03, 2013
at 02:56 PM

Yep it definitely holds in diabetic humans, probably because the enzyme allows them to make glucose from ketones. Increasing insulin sensitivity seems to be the most obvious answer so far. +1 for your supertheory of supereverything.

A2c38be4c54c91a15071f82f14cac0b3

(12682)

on May 02, 2013
at 07:43 PM

Yeah I went looking for any important functions and the main thing I found was its role in the only known pathway of net glucose production from fatty acids. There are probably others, but nothing readily apparent. At the very least I think inhibiting it might be something to look into during heavy alcohol consumption, since ethanol induces CYP2E1.

A2c38be4c54c91a15071f82f14cac0b3

(12682)

on May 02, 2013
at 07:23 PM

Well, the main route of detoxifying acetominophen is through conjugation which is a significantly less toxic method of getting rid of it. But yeah, for something with no other route of removal you might have a point.

F5a0ddffcf9ef5beca864050f090a790

(15515)

on April 30, 2013
at 07:22 AM

I wonder if anybody is going to answer your question. Have you tried asking your biochemistry professor?

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3 Answers

1
Cb9a270955e2c277a02c4a4b5dad10b5

(10989)

on May 03, 2013
at 02:26 PM

If There is an increased expression of cyp2e1 in t2 diabetic mice and if that association holds in humans then it would make sense that lifestyle activities that are most protective against insulin resistance, t2 diabetes and metabolic syndrome might also be protective against and possibly down regulate or just normalize otherwise increased Cyp2e1 expression. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425959/ .

Since you're a regular and most regulars here already know my bent you probably know that I'm going to TF say to avoid sedentary behavior and encourage vigorous exercise. GL finding your answer mscott :).

A2c38be4c54c91a15071f82f14cac0b3

(12682)

on May 03, 2013
at 02:56 PM

Yep it definitely holds in diabetic humans, probably because the enzyme allows them to make glucose from ketones. Increasing insulin sensitivity seems to be the most obvious answer so far. +1 for your supertheory of supereverything.

Cb9a270955e2c277a02c4a4b5dad10b5

(10989)

on May 03, 2013
at 03:33 PM

Like, I really think there's a reason Jack Lalanne lived to be 96 and died of, respiratory failure? I think. Study after study is showing the importance of exercise in cancer, diabetes, CHD, ability to control or lower inflammation, even in oral health. It all fits together nicely with the mitochondrial theory of disease I posted a while ago. The biggest questions left IMO are which physical activities are best (lots of options from CT to Sprint 8, walking, gardening, yoga), how dangerous is sedentary behavior independent of exercise, how important is diet, and how do these things interact.

Cb9a270955e2c277a02c4a4b5dad10b5

(10989)

on May 03, 2013
at 03:26 PM

Lol, thanks mscott, I'm still working on it though, now I'm just trying to learn more about the metabolic syndrome, chronic inflammation and seeing if there's a possible way to tie that together with maybe mitochondrial function and degenerative chronic diseases. I'm really thinking that physical activity of some sorts is going to show to be the connecting mechanism between all these things, assuming an otherwise adequate diet (but not necessarily a perfect diet).

1
32f5749fa6cf7adbeb0b0b031ba82b46

(41757)

on May 02, 2013
at 03:58 PM

The question is what else is CYP2E1 doing and what effects would down-regulating it have. I'd be weary of mucking around with a singular enzyme for a specific purpose. Not a biologist, but all these enzymes doing oxidation chemistry seem important, too important to knockdown or inhibit without previous overexpression or upregulation.

A2c38be4c54c91a15071f82f14cac0b3

(12682)

on May 02, 2013
at 07:43 PM

Yeah I went looking for any important functions and the main thing I found was its role in the only known pathway of net glucose production from fatty acids. There are probably others, but nothing readily apparent. At the very least I think inhibiting it might be something to look into during heavy alcohol consumption, since ethanol induces CYP2E1.

1
7bf306ada57db47547e9da39a415edf6

(11214)

on May 02, 2013
at 03:19 PM

I suspect things would far worse if CYP2E1 didn't metabolize acetaminophen into NAPQI. This is part of trying to handle an agent that probably shouldn't be in the body. We see damage occuring downstream, if there isn't enough glutathione, but if the acetaminophen wasn't metabolized at all serious damage would occur elsewhere.

So, it is probably a good idea not to take stuff that needs to be processed this way, but not a good idea to inhibit the enzyme. It will down regulate anyway once you prove to your liver you aren't stupid enough to eat acetaminophen, but you do want your body to be able to respond in an emergency.

Personally, I can't wait for a glutathione with a non-soy based delivery system that is cheap enough to take every day. I've tried the s-acetyl-glutathione. It works, but it is expensive at any dosage, and at what seems to be the best dose for me (though I am not sure) it is downright ridiculous.

A2c38be4c54c91a15071f82f14cac0b3

(12682)

on May 02, 2013
at 07:23 PM

Well, the main route of detoxifying acetominophen is through conjugation which is a significantly less toxic method of getting rid of it. But yeah, for something with no other route of removal you might have a point.

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