Your liver is quite the multi-tasker. Its most important job is to detoxify foreign chemicals, but it also does a number of other important tasks, including regulating blood sugar levels, making bile to help digest fats, making your blood’s carrier proteins and clotting factors, acting as a repository for a number of nutrients (including iron, copper, B12, and your fat soluble vitamins: A, E, D, and K), packaging your triglycerides into cholesterol, and breaking down triglycerides for use as energy.

But these jobs take a backseat to detoxification. There are two steps in the liver’s detoxification process, aptly named Phase 1 and Phase 2.

Phase 1 Detoxification

The purpose of Phase 1 is generally to render chemicals less toxic than they were before. The liver does this using specific cytochrome P450 enzymes, each with their own toxin specialties. Phase 1 often briefly creates free radicals, which isn’t a big deal as long as the liver’s antioxidant supply is up to the task of quenching them. When the antioxidant status is low (either due to low dietary intake or prolonged toxic exposure), this can become dangerous, though.

Phase 1 can slow down due to lack of blood flow, which might be due to aging or to lack of physical activity. It can also slow down due to deficiency in the vitamin and mineral cofactors necessary for the enzymatic function (including Vitamins B2 and B3, magnesium, and iron). Heavy metal toxicity can also be especially damaging to this phase.

On the other hand, an excessively fast Phase 1 process can be a problem if paired with a slowdown in Phase 2; in this case, the antioxidants will also get overtaxed with the excessive free radicals (unpaired electrons) to quench, and you’ll likely end up with oxidative damage as well as chemical sensitivity.

Phase 2 Detoxification

Once toxins have been through Phase 1, the job of Phase 2 is to add a side group on to the often fat-soluble or insoluble intruders, in order to render them water-soluble and ready for elimination.

There are six main pathways that chemicals can take in Phase 2. Some chemicals can go through more than one of them.

The Sulfation Pathway: This pathway adds a sulfate group (SO2-4) to a number of chemicals including endotoxins from bacteria, Tylenol, and a number of environmental toxins including Bisphenol A and xenoestrogens (chemicals that behave like estrogen in the body). It’s also the primary pathway for the elimination of adrenal and sex hormones, thyroid hormones, and neurotransmitters.

The sulfur in the sulfate group comes from amino acids that contain sulfur (methionine and cysteine), and also requires molybdenum, B12, folate, magnesium, B6, SAMe, and taurine. Those with sulfur intolerance will have to be careful about consuming too many sulfur-containing amino acids, though. 

The Glucuronidation Pathway: glucuronic acid is derived from glucose. The liver adds this side group to medications like aspirin, food additives like benzoates, preservatives, and it also tacks these on to steroid hormones.

This process needs magnesium also, and B vitamins. (Calcium D-glucarate, a common supplement added for estrogen elimination, helps with this process.)

The Glutathione Transferase Pathway: Glutathione is not only the major antioxidant for the liver in quenching free radicals produced in Phase 1; it’s also one of the side groups added in Phase 2. Glutathione transferase, the enzyme that adds glutathione to chemicals, usually tackles heavy metals, solvents, pesticides, and PAHs.

This process requires the glutathione amino acid building blocks: cysteine, glutamic acid, and glycine. You can also increase regeneration of glutathione with other antioxidants, such as Vitamin C and Alpha Lipoic Acid.

The Acetylation Pathway: One of the most ubiquitous biochemical processes in the body (glycolysis) produces an end product called pyruvate, which then becomes Acetyl CoA (through pyruvate oxidation in the mitochondrial membrane). Normally this molecule goes on to turn into ATP, the body’s energy currency, but in the liver it is also used as one of the Phase 2 detoxification side groups. Acetyl CoA attaches to histamine, serotonin, salicylic acid, tobacco and car exhaust.

It requires molybdenum, iron, Vitamins B1, B2, B3, B5, and Vitamin C.

The Amino Acid Conjugation Pathway: the amino acids used include glycine, taurine,  glutamine, arginine, and ornithine. This pathway eliminates toluene (a solvent), benzoate (a food preservative) and other chemicals from the environment. This process also requires the body to be alkaline and not acidic.

Since amino acids are the building blocks of protein, this process requires eating plenty of protein. It also requires co-factors folic acid, manganese, and Vitamins B2 and B6.

The Methylation Pathway: this one has probably gotten the most attention lately, with the infamy of MTHFR mutations. Methylation involves adding a methyl group (-CH3) to various kinds of hormones, neurotransmitters, or toxins to render them water soluble. The amines (serotonin and melatonin, histamine, tyramine, all the catecholamines including dopamine, norepinephrine, epinephrine) go through this pathway. So do phenols (like salicylic acid—aspirin, cannabinoids, estradiol, and BPA) and quite a few other chemicals. Genetic mutation anywhere in the methylation cycle can therefore mean mental/emotional imbalance, migraines, hormone imbalance (especially estrogen dominance), and toxicity.

The main methyl group donor comes from the amino acid methionine, which gets converted into SAMe. SAMe donates a methyl, and if it doesn’t get recycled back into methionine to continue the process, it can get broken down into cysteine, where it can either turn into a sulfate (for the sulfation pathway above), or it can get turned into glutathione (for the glutathione transferase pathway, or as an antioxidant for Phase 1.) No waste here.

This pathway requires Vitamins B12, folic acid, magnesium, choline, methionine, betaine, and molybdenum.

The Upshot:

Phase 1 makes substances less toxic, but potentially turns them into free radicals which requires a lot of antioxidants. There are many different, chemical-specific enzymes for this process. If this is fast but some aspect of Phase 2 for final elimination is slow, you’ll probably be chemically sensitive.

Phase 2 involves adding side groups to the substrates from Phase 1 to make them water soluble for elimination. This somewhat depends on the kind of chemical, but there are far fewer enzymes to choose from at this step.

Genetic analysis will tell you if you’ve got a slowdown at ether Phase 1 or Phase 2, thereby implying which nutrients you need to supplement to help the enzymes work as well as they can. There are a number of companies that do this test; the one I generally use is 23 & Me, and then take the PDF they send and plug it in to for a full analysis.