Liver detoxification pathways and enzymes

Tiana Tallant Uncategorized

I have spent the last few weeks diving head first into all the nitty gritty detail around liver detoxification pathways and the enzymes responsible for metabolizing different substances.  

My understanding of the science is that we still know very little about how certain foods and specific nutrients impact particular enzyme activity. Research is conflicting as studies have demonstrated that certain foods/ nutrients may have a particular effect (inducing/ inhibitory) on an enzyme at a certain dose while having the opposite effect at higher doses. 

This quote sums it up nicely…

“Resulting clinical takeaway might be to encourage clients to follow a mixed, varied diet, full of different plant-based whole foods. Smaller amounts of specific compounds might be more therapeutic and supportive for biochemical pathways rather than overriding signals derived from high concentrations of nutrients through high-dose supplementation or the repeat daily ingestion of large quantities of the same food.”

I don’t know how many other ways to say it. But it is nice when multiple researchers continue to come to the same conclusions. 

Below is some in-depth nerdy information if you like that kind of thing.  

xo

Tiana


Overview: liver detoxification requires 2 phases. In phase I, an oxygen molecule is added to form a reactive site on the toxic compound. During phase II, a water soluble group is added to this reactive site so that the compound becomes water soluble and is able to be excreted in urine or bile (in poop). It is important to note that overactivity of any of the phase I enzyme families (without adequate phase II enzyme support) is problematic as it produces reactive intermediate compounds that are electrophilic- that is they’re trying to pick up other electrons.

Cytochrome P450 enzymes are the phase I enzymes that are used to biotransform xenobiotics (foreign substances), steroid hormones, and pharmaceuticals. They are found primarily in liver but also in enterocytes (in intestines), kidneys, liver, and the brain. These enzymes add a reactive group to these compounds as discussed above. 

CYP1 enzymes: This family is involved in metabolizing procarcinogenic substances (substances that are precursors to carcinogens- they are not carcinogenic on their own- but are transformed into carcinogens by the body- including nitrites), hormones, and pharmaceuticals. CYP1 enzymes are involved in estrogen metabolism (specifically 2-OH and 4-OH). 4-OH estrogens tends to be particularly problematic which is why tests like @dutchtest look at the different estrogen metabolism pathways. 

CYP2 enzymes are involved in the metabolism of drugs, xenobiotics, hormones, and other endogenous compounds such as ketones, glycerol, and fatty acids

CYP3 enzymes. CYP3A4 is responsible for metabolism of caffeine, PAH’s (think general air pollution from fossil fuels), testosterone, progesterone, and androstenedione. Grapefruit is the most well known inhibitor of this enzyme. Curcumin has been shown to upregulate enzyme activity. Research has been mixed on results of sulforaphanes and I3C -with studies demonstrating both inhibition and increased activity.


Phase II Conjugation enzymes

UDP-Glucuronosyltransferases. This family of enzymes plays an important role in metabolizing steroid hormones and bilirubin. Cruciferous veggies, resveratrol, citrus have been found to induce enzyme activity.

Sulfotransferases. Decreased function of these enzymes can lead to alterations in thyroid hormone, estrogen, and androgen levels. Once compounds have been conjugated with sulfate- they are less reactive and toxic. Enzyme activity is dependent on depletable reserve of sulfate- therefore dietary sources may play an essential role in the function of this enzyme. Sources of sulfur include allium veggies and cruciferous  veggies, organic eggs, wild caught fish, grass-fed beef.

Glutathione S-transferase. These enzymes attach a glutathione group to metabolites. Cruciferous and allium veggies (more powerful effect in women) and resveratrol have been found to induce GST activity in humans. Support for glutathione conjugation involves enhancing reduced glutathione (GSH) status. GSH is made from cysteine, glutamate, and glycine. Methionine and cystine are important precursors to glutathione formation. NAC has also been used to support GSH status. B6, magnesium, and selenium may enhance endogenous glutathione synthesis. Curcumin, silymarin (milk thistle), folic acid, and alpha lipolic acid have been shown to restore depleted GSH status.

Amino acid transferases. Amino acids of various types can be utilized for attaching to molecules for excretion. THIS IS WHY dietary protein is essential for excellent detoxification

N-acetyl transferases (NAT). Not much is known about how dietary nutrients impact NAT function

Methyltransferases. The conjugating donor in methyltransferase reactions is a methionine group from s-adenosyl-L-methionine (SAMe). Catechol O-methyltransferase (COMT) is one of the prominent members of this family d/t its role in estrogen detox. Support for methylation consists of nutrient cofactors and methyl donors such as methionine, B12, B6, betaine, folate, and magnesium. This is also my favorite reason to have clients supplement creatine- as 50% of our bodies methylation resources go to creatine production- so it would make sense that if we have adequate creatine levels, that our body can dedicate methylation resources elsewhere- like to detoxification.

The transcription factor, Nrf2, is key to regulating the body’s detoxification and antioxidant system. Nrf2 deficient animals experience increased toxicity from drugs, carcinogens, allergens, and environmental pollutants and do not respond well to the anti-inflammatory effects of phytochemical. Research demonstrates that dietary components especially phytochemicals (fruits/ veggies) not only scavenge reactive oxygen species, but also regulate Nrf2 activity. 

Metallothionein. A cysteine-rich protein with ability to bind mercury, cadmium, lead and arsenic. It is also capable of scavenging free radicals and reducing injury from oxidative stress. Quercetin and cordyceps may help upregulate expression. 


I think the most appropriate way to wrap up this post is to return to the initial comments…

“Resulting clinical takeaway might be to encourage clients to follow a mixed, varied diet, full of different plant-based whole foods. Smaller amounts of specific compounds might be more therapeutic and supportive for biochemical pathways rather than overriding signals derived from high concentrations of nutrients through high-dose supplementation or the repeat daily ingestion of large quantities of the same food.”

Ironically, we are left with the same suggestions as always.

Drink water

Eat a variety of plants

Eat adequate protein

Be mindful of the toxin load you are placing on your system

More “supportive” nutrients might not always be better


Reference

Modulation of Metabolic Detoxification Pathways PMID: 2616729