Key takeaways:
- The body eliminates harmful substances through a three-phase process.
- Phase I detoxification generally involves the CYP450 enzymes, which break down substances to make them more polar. This phase often produces reactive or toxic metabolites.
- Phase II takes the reactive metabolites from phase II and adds another molecule to make them safer and more water-soluble for elimination.
- The third phase involves transporting the substances out of the cells and then elimination from the body.
- Genetic variants in all of these pathways affect how easily you detoxify specific substances.
Detoxification and Genetic Pathways:
Your body is remarkably capable of ridding itself of harmful substances through a complex of detoxification pathways.
We are all exposed to various toxicants (manufactured toxins) through pesticide residue, air pollution, skin care products, and medications. In addition, our bodies break down and eliminate substances made and used within ourselves, as well as natural plant compounds. All of these processes rely on interconnected systems to metabolize and eliminate toxins.[ref]
Genetic variants can impact how medications and toxicants are broken down and eliminated, making us all unique in how we detoxify substances. Understanding where you have a genetic susceptibility — and then optimizing to avoid specific toxicants or drugs — is the key here.
“Detox” isn’t just drinking a juice cleanse or supporting liver health. Instead, it is a biotransformation system that continuously converts harmful substances into water-soluble compounds to remove them from the body.
Let’s first look at the big picture: how phase I, phase II, and phase III detoxification work in general. Then you’ll find links to the detailed articles + genotype reports on variants in these pathways. The goal is that by understanding how your body eliminates specific substances, such as prescription drugs and pesticide residue, you can make informed decisions about what is likely to be important for you.
Detoxification pathways:
Detoxification pathways are the body’s way of metabolizing (breaking down) foreign substances and then eliminating them. This is usually a two- or three-stage process.
In a nutshell, substances need to be water-soluble to be eliminated via feces and urine, and the goal of ‘detox’ is to get rid of substances that are harmful.
Three phases of detoxification:[ref]
- Phase I (bioactivation transformation) involves breaking apart large toxins and converting them into polar molecules. This process is called metabolism, and the resulting substances are called metabolites.
- Phase II (conjugation) then binds a molecule to the metabolite from Phase I, making it water-soluble and easily excretable.
- Phase III (transport and elimination) involves specialized transport proteins to pump the phase II conjugated toxins out of the cells. These substances are then moved into the bile or kidneys for elimination (urine, feces).
Why an imbalance between Phase I and II matters:
Phase I detoxification processes often make a lipophilic (lipid-soluble) substance more hydrophilic for increased solubility. This step sometimes results in a substance that is even more toxic than the original — a toxic metabolite.
Phase II processes then need to come along and remove that toxic metabolite by conjugating it with another molecule that will facilitate its elimination. If phase II processes can’t handle the load of toxic metabolites, then cell damage can occur. (DNA damage is the biggest problem because it can lead to cancer-causing mutations.)
How do phase I and phase II metabolism apply to medications or drugs?
These detoxification pathways are particularly relevant when it comes to the way drugs will work for an individual.
The rate at which a medication is metabolized affects how your body will react to that drug:
- Too fast, and you may not get the effect you need.
- Too slow, and you may build up too much in your body when you take the next dose.
Some medications are designed so that the metabolite – the substance created after phase I metabolism – is actually the active drug. These types of medications are called prodrugs. Phase I metabolism must take place in order for the active drug to be formed.
Note: While genetic data from services like 23andMe or AncestryDNA can provide part of the picture on medication metabolism, for a better understanding of your drug metabolism issues, your doctor may recommend getting a clinical-grade test done. This type of testing is called pharmacogenetic testing and can give a prescribing doctor a clear picture of which drugs are likely not to work well for you.
Phase I Detoxification Genes: CYP450 Family
Many toxicants – whether ingested, inhaled, or created in our bodies – are broken down by the Cytochrome P450 (CYP450) family of enzymes in phase I detoxification. This process primarily occurs in the liver, the body’s main organ for detoxification.[ref]
The CYP450 enzymes have iron and oxygen in them and, through a redox reaction, can make a drug, toxin, or endogenous substance more polar. These metabolite molecules then pass through phase II detoxification to become even more hydrophilic (water-loving) so that they can easily be eliminated. The goal of these detoxification pathways is to create molecules that the body can easily get rid of (urine, feces, sweat).[ref]
CYP450 Genetic Variants:
Genetic variants in CYP450 enzymes can significantly impact how an individual metabolizes various toxicants, medications, and substances produced within the body. Read through the article and check the genotype report. Members can start with the Detoxification Topic Report to easily see which articles are important to read first.
- CYP1A1 – metabolism of estrogen, polyaromatic hydrocarbons, and more
- CYP1A2 – metabolism of caffeine, duloxetine, bupropion, aflatoxin B, and more
- CYP2A6 – metabolism of nicotine, coumarin, and more
- CYP2B6 – metabolism of ketamine, methadone, sertraline, and more
- CYP2C9 – metabolism of warfarin, rosuvastatin, celecoxib, and more
- CYP2C19 – metabolism of clopidogrel, some proton pump inhibitors, more
- CYP2D6 – metabolism of some antidepressants, antipsychotics, more
- CYP3A4 – metabolism of half of all prescription drugs
- CYP2E1 – metabolism of fatty acids, alcohol, and some anesthetics
Phase II detoxification genes: UGT, GST, Nrf2
Phase II detoxification involves taking the metabolites of phase I and modifying them to be easily excreted through conjugation with sulfur, glutathione, glucuronic acid, amino acids, or methyl groups.
Many of the metabolites of phase I are carcinogenic or reactive, so having phase II detox in sync is very important. Fast and efficient phase II metabolism keeps toxic metabolites moving out of the body quickly.
The following articles explain your genetic susceptibility variants related to phase II detoxification, nutrients and cofactors needed for optimal support, and how to prioritize what is most important for you, personally, to avoid.[ref]
- Nrf2 Signaling Pathway– master switch inducing the phase II enzyme pathways, upregulated by sulforaphane [ref]
- UGT genes – glucuronidation, most prevalent phase II enzyme
- GST genes – glutathione conjugation reactions
- SULT genes – sulfation reaction increases the water solubility of drugs, hormones, and xenobiotics.
- NQO1 – metabolizing benzene, quinones, air pollution
- NAT1 and NAT2 – N-acetyltransferases, cigarette smoke, hydrocarbons
- COMT – adds methyl groups to modify endogenous substances, including estrogen, for elimination
Elimination: Phase III Transporter Proteins
Phase I and Phase II happen inside your cells, but once a metabolite has been made water-soluble, it still has to physically leave the cell and then the body. That is where phase III comes in – moving the phase II conjugated metabolites across cell membranes and out toward the bile or urine. It’s run by a set of dedicated transporter proteins. Phase III transporters in the liver and intestine remove xenobiotics and their metabolites from cells, and they’re key to eliminating the toxins completely from the body. Genetic variants in the cellular transporter proteins can also affect how your detoxification pathways function.[ref]
Bile acids are essential in the process, as is proper kidney function. You can promote elimination by staying hydrated (peeing it out) and by normal bowel movements (pooping regularly). Additionally, some substances can be eliminated through sweat. With all of these routes of elimination, getting enough water each day is important – as is having regular bowel movements. The gut microbiome can also play a significant role in how conjugated toxins are moved out through feces – or absorbed back into the body.[ref]
- ABCB1 – P-gp efflux transporter for medications, HRT, and environmental toxins
- SLCO1B1 and ABCG2 – statins and muscle pain risk
- OCTN1 – organic cation transporter, ergothionine
Detoxification pathways for specific substances:
In addition to the phase I and phase II specific genes above, the following articles look at specific toxicants and their detoxification pathways:
- Mold Genes
- Arsenic Detoxification
- BPA Detoxification
- Glyphosate Detoxification
- Organophosphate Pesticides
- Caffeine Metabolism
- Phthalate Detoxification
- Lead
- PFAS
- Fluoride
- DPYD 5-fluorouracil toxicity
- Mercury
- Molybdenum and copper
- ALDH2, ADH1B and Alcohol
By learning about your genetic variants and their impact on detoxification pathways, you can take proactive steps to support your body’s natural ability to eliminate harmful substances and maintain optimal health.
This article is part of the Detoxification and Medication Genetic Lifehacks Hub.
References:
