Most people reading this are aware that the liver is involved in detoxification. However, many don’t realize how complex of a system this is, as there are many different factors that can affect the detoxification pathways. And if any one of these factors are negatively impacted then you very well might have problems with detoxification. Plus, remember that detoxification isn’t just about removing harmful chemicals, but hormones as well, including thyroid hormone, estrogen, etc. There is so much to discuss that I’ve decided to split this up into two different blog posts, as in this post I will talk about how to optimize phase one detoxification, and in the next post I will focus on how to optimize phase two detoxification.
One thing I do want to point out is that while most detoxification takes place in the liver, keep in mind that the gut, lungs, kidney, and skin also play a role in detoxification. As a result, if one or more of these other areas are compromised then this can affect detoxification. For example, I’ll be talking about the CYP enzymes, which play a role in phase one detoxification. And while these enzymes are primarily located in the liver, they are also located in the gut as well. And this is one reason why having a healthy gut is important for optimal detoxification.
Understanding The Basics of Detoxification
Phase one detoxification is all about the transformation of fat soluble compounds into reactive intermediates. I’ll explain what this means in a minute, but I first want to mention that this transformation requires the help of the CYP enzymes I briefly mentioned earlier, which I’ll expand on shortly. While I’ll be focusing on phase two during the next blog post, I did want to mention here how this phase is involved in conjugation with the reactive intermediate to form a water soluble metabolite that will get excreted.
In order to better understand this let’s look at an example. If someone uses a skincare product that includes a xenobiotic (a foreign chemical substance), as part of the phase one detoxification process the liver will use certain enzymes to transform this chemical, which in turn will become water soluble after the phase two reactions. The same concept applies when someone is eating a vegetable with pesticides, as the body will transform the chemicals that are in the pesticide, and eventually these chemicals will become water soluble.
This is a simplified example, as in phase one what frequently happens is that the transformation process turns the environmental toxin into a more harmful reactive intermediate. This in turn can form free radicals and cause damage to your DNA, RNA, and proteins. And while a properly functioning phase two system is important for the detoxification of these chemicals, you need an abundance of antioxidants to help minimize the damage caused by these reactive intermediates produced in phase one.
So for example, if someone doesn’t eat a good amount of fresh vegetables and fruits, which are filled with antioxidants, then this will lead to increased damage during phase one detoxification. Taking antioxidant supplements such as vitamin C, vitamin E, and glutathione can also help to some extent, but you need to eat a healthy diet in order to minimize any negative reactions from phase one detoxification. In addition, certain factors can induce phase one activity. In other words, certain factors can speed up the transformation that takes place in phase one. This might sound like a good thing, but if someone doesn’t have sufficient antioxidants, or if there are problems with their phase two detoxification pathways, then this can cause a lot of oxidative stress, which of course isn’t a good thing.
The Role of The Phase One Detoxification Enzymes
Earlier I mentioned how certain enzymes are required for phase one detoxification, and these are called cytochrome P450 enzymes. These enzymes are necessary for the biotransformation process. However, certain nutrients, herbs, and drugs can either induce (i.e. speed up) or inhibit these enzymes. Having certain genetic defects can also affect these phase one detoxification enzymes. But what’s the significance of this? Well, if something induces one of these CYP450 enzymes, then this increase in enzyme activity can in turn cause an increase in the reactive intermediates, which can cause further damage…unless if the phase two system is upregulated as well. On the other hand, downregulating or slowing down these enzymes to some extent can be beneficial. In other words, while you don’t want to completely inhibit these phase one enzymes, taking certain nutrients to slow down the activity of phase one detoxification can reduce the oxidative stress and damage.
It’s also important to understand that inhibiting or inducing these enzymes can cause problems when someone is taking one or more medications that are metabolized by the same enzyme. Let’s look at an example of this. CYP3A4 is a phase one enzyme that is involved in the metabolism of many drugs. And grapefruit juice has compounds that can inhibit the CYP3A4 enzyme. As a result, if someone is taking a certain drug that is metabolized by the CYP3A4 enzyme and the same day they take the drug they decide to drink some grapefruit juice, then this will decrease the metabolism of this drug, causing it to build up in the system. On the other hand, the herb St. John’s Wort can lead to an increase in the metabolism of the CYP3A4, which can decrease the effectiveness of certain drugs. This is one reason why St. John’s Wort is contraindicated when taking certain medications.
Does this mean you should never drink grapefruit juice or take St. John’s Wort? Of course not, but if you are taking medication you might want to do some research to see if it is metabolized by the CYP3A4 enzyme, and if this is the case you probably would want to refrain from drinking grapefruit juice or taking St. Johns Wort. Click here  for a list of drugs that are metabolized by CYP3A4 and 3A5. For those who take bioidentical hormones, you’ll notice that CYP3A4 and 3A5 metabolizes estradiol, progesterone, and testosterone. The point I’m trying to make is that nutrients or herbs that inhibit or slow down these phase one enzymes can cause certain drugs to build up in the bloodstream, while speeding up the enzymes will increase the metabolism of certain drugs, which can reduce their effectiveness.
Understanding Some of The Phase One Detoxification Enzymes
What I’d like to do below is discuss a few of the more common CYP450 enzymes so you can better understand how they help to biotransform certain chemicals in the body. However, it’s important to understand that these enzymes can have multiple roles. For example, I’ll discuss how the CYP1A2 enzyme plays a role in metabolizing caffeine, but this enzyme is also important for estrogen metabolism.
Let’s go ahead and take a look at some of these enzymes:
CYP3A4 and 5. As I mentioned earlier, the CYP3A4 enzyme is primarily involved in drug metabolism, and it is involved in the metabolism of certain hormones. The CYP3A5 enzyme also is involved in drug metabolism. In fact, 40 to 45% of all drugs are metabolized through these enzymes. This includes acetaminophen, codeine, cyclosporin A, diazepam and erythromycin (1) .
Earlier I mentioned how grapefruit juice can inhibit the CYP3A4 enzyme, which can cause certain medications to build up in the bloodstream. Other agents that can inhibit this enzyme include antifungal medications, along with resveratrol. I also mentioned how St. John’s Wort can cause induction of this enzyme, which in turn will speed up the clearance of certain medications from the body. Red wine and licorice root can also induce this enzyme.
Can Grapefruit Juice Affect Thyroid Hormone Metabolism?
Getting back to grapefruit juice, one small study looked at the effect of grapefruit juice on levothyroxine metabolism (2) . The study showed that grapefruit juice might slightly delay the absorption of levothyroxine, but it only has a minor effect on its bioavailability. I couldn’t find any studies which showed if grapefruit juice can affect the absorption or bioavailability of antithyroid medication, but one study I came across showed that methimazole can cause a dramatic decrease of CYP3A4 activity, while partially decreasing the activities of some other CYP enzymes (3) . What this means is that if someone is taking one or more medications along with Methimazole, and if those medications are metabolized by the phase one detoxification enzymes that are affected by Methimazole, then the blood levels of some or all of these can be greatly increased.
CYP2D6. This enzyme is involved in 25-30% of drug metabolism, as it helps to transform many antidepressants, antipsychotics, analgesics and antitussives, some beta blockers, antiarrythmics and antiemetics (4) . CYP2D6 genetic polymorphisms are very common (4) . Smoking cigarettes and eating charlbroiled meat can induce this enzyme (5)  (6) . So if someone is taking a medication that is metabolized by the CYP2D6 enzyme and is a smoker, or eats a very well-done grilled hamburger, then this can actually increase the metabolism of the drug.
Earlier I mentioned how CYP2D6 genetic defects are very common. Tamoxifen is one of the drugs metabolized by CYP2D6, and this drug is commonly recommended as a treatment for some cases of breast cancer. And just to show the impact these phase one enzymes can have, one research study shows that after taking tamoxifen for five years, women who had reduced CYP2D6 metabolism had an increased incidence of relapsing or dying at a rate that was 2.5 times higher than women with normal CYP2D6 (7) . In other words, if someone has a genetic polymorphism of the CYP2D6 gene, then they probably shouldn’t be given tamoxifen. Fortunately this can be tested for, which I’ll talk more about shortly.
CYP1A2. Although this enzyme is involved in the biotransformation of some drugs, it also plays a big role in the metabolism of caffeine. I’ve spoken about this in a past blog post , as if someone has an upregulated CYP1A2 gene then they are considered to be a fast metabolizer of caffeine, and thus they are able to clear caffeine rapidly from the body. On the other hand, if someone has a downregulated CYP1A2 gene then they will be a slow metabolizer of caffeine, and these are usually the people who have problems sleeping when drinking coffee, especially later in the day. The CYP1A2 enzyme is also important in the biotransformation of 2-OH estradiol, which is considered to be one of the “good” estrogen metabolites.
CYP1B1. This enzyme helps to transform certain pro-carcinogenic (cancer causing) chemicals into reactive intermediates. For example, it helps to transform estrogen into the 4-OH metabolites, which is considered to be a “bad” estrogen metabolite. Other chemicals can induce the CYP1B1 enzyme, such as PCBs, the chemicals in cigarette smoke, UV light, and even xenoestrogens. In other words, exposure to these chemicals will cause the body to convert more of these chemicals into reactive intermediates.
Is this a good thing or a bad thing? Well, it can be a good thing if you have a properly functioning phase two system (which I’ll talk about in the next blog post), as this will help to convert these reactive intermediates into water soluble molecules that will be excreted. On the other hand, if someone has problems with their phase two detoxification pathways then these reactive intermediates can build up, which can increase the risk of cancer and other chronic health conditions.
But even if they have a properly functioning phase two system, if they are exposed to a high amount of environmental toxins then this still can be a problem, and in this case you might want to do things which can inhibit or downregulate this enzyme. CYP1B1 is downregulated by DHEA, polyphenols, resveratrol, and pomegranate. So if someone is exposed to large amounts of cancer-causing chemicals which are transformed into reactive intermediates, it probably would be a good idea to increase your consumption of polyphenol by consuming more vegetables, fruits, and spices, or perhaps you can take some resveratrol or eat some pomegranate.
CYP2E1. This enzyme is involved in the metabolism of many different chemicals, including acetaldehyde, acetaminophen, acrylamide, aniline, benzene, butanol, carbon tetrachloride, diethylether, dimethyl sulfoxide, ethyl carbamate, ethylene chloride, halothane, glycerol, ethylene glycol, N-nitrosodimethylamine, 4-nitrophenol, pyrazole, pyridine, and vinyl chloride (8) . It is induced by ethanol, benzene, and styrene, and inhibited by grape seed extract, resveratrol, garlic, licorice root, and watercress.
It’s important to keep in mind that when I list certain nutrients, or herbs, and medications that can induce or inhibit a specific enzyme, these are just a few examples. You’ll notice that with some enzymes I’ll list more inducers and inhibitors than others, and one reason is because with some enzymes we have a greater knowledge of the inducers and inhibitors. And unfortunately there is the possibility that there are nutrients, herbs, and drugs which can induce or inhibit a specific enzyme but this hasn’t yet been discovered.
The Role Of Diet In Phase 1 Detoxification
Although phase two is more dependent on nutrients, eating well in phase one is of course important. Earlier I spoke about the importance of antioxidants in helping to minimize the damaging effects of the reactive intermediates formed in phase one detoxification. And while you can take antioxidant supplements, you really do want to make sure you eat a good amount of antioxidant rich foods such as vegetables, fruit, and even certain beverages such as green tea. It’s also important to know that the CYP450 enzymes are heme-dependent, which means that they require iron to function properly.
This is one of the reasons why I have just about all of my patients get a full iron panel. It’s also important to know that fasting can induce certain CYP450 enzymes. This includes CYP2B1, CYP2B2, and CYP2E1 (9) . So in other words, fasting can help to increase the metabolism of these enzymes, which can increase the clearance of certain chemicals. While this might sound like a good thing, if someone is exposed to a lot of environmental toxins and/or has inefficient phase two detoxification pathways, then this can lead to the buildup of reactive intermediates and make the person feel sick. I’m not suggesting that fasting is never a good idea, but you do want to be cautious.
This might explain why many people (although not everyone) feels better when doing a juice fast, while some people might feel lousy when doing a water fast for a few days. A juice fast involves plenty of antioxidants, which helps to quench the free radicals produced in phase one, but the nutrients in the fruits and vegetables also help to support phase two detoxification. The problem is that phase two detoxification also requires sufficient protein, and so while there have been some great success stories involving people who did a juice fast for a prolonged period of time, it can also be problematic if you do it for too long.
How Genetic Mutations Can Affect Phase One Detoxification
I’m not going to get into great detail about genetic polymorphisms (SNPs), which are common genetic mutations. But one can’t overlook these, as if someone has a genetic defect of one or more of the phase one detoxification enzymes then this can cause a lot of problems. For example, in this blog post I mentioned how CYP3A4 and CYP2D6 are both involved in the metabolism of many different medications. And if someone has a genetic defect in one or both of these phase one detoxification enzymes then this can affect the absorption of medications that are metabolized by these enzymes. And of course people can have genetic polymorphisms of other phase one detoxification enzymes as well.
So the next question you probably have is…”how can I determine if I have a genetic polymorphism of the CYP3A4 or CYP2D6 enzyme, or other phase one detoxification enzymes?” Fortunately genetic testing is available, as many labs offer it, and many people use a company such as 23andme, although this also requires using a third party service such as Genetic Genie or Nutrahacker to list the specific genetic polymorphisms. If a medical doctor prescribes a drug that is metabolized by one of these enzymes, it would be a good idea to have the person do some genetic testing, although I realize that there are times when time is a factor and the person might need to take a certain medication sooner than later. This is one reason why I think that genetic testing will become more routine in the future, as there will be a time and place when medical doctors will take into account the person’s genetics when prescribing certain medications.
What’s The Best Way To Support Phase One Detoxification?
I realize that this blog post was advanced for some people, and so I’ll summarize everything here so that you will better understand how to support and optimize phase one detoxification.
1. Consume plenty of antioxidants. You learned that phase one involves the transformation of fat soluble molecules into reactive intermediates. And so one thing you want to do is to make sure you consume plenty of antioxidants. While taking supplements to increase glutathione production is something some people need to consider, you also want to eat plenty of antioxidant-rich foods, such as vegetables, fruits, and green tea.
2. Downregulate phase one detoxification enzymes. You also learned about inhibiting and inducing phase one enzymes. While there can be benefits of both induction and inhibition, the main concern with inducing one or more of the phase one enzymes is that it can lead to an excess of reactive intermediates. And so typically you will want to do things to inhibit or downregulate these phase one enzymes. And while different nutrients are required to inhibit certain enzymes, some of the more common nutrients that can help to slow down the phase one enzymes include resveratrol, polyphenols, pomegranate, and garlic.
3. Consider doing genetic testing. You also might want to consider doing some testing to determine which genetic polymorphisms of the phase one detoxification enzymes you have. Notice I didn’t say “if” you have genetic polymorphisms, as pretty much everyone has certain genetic polymorphisms, although some are more significant than others. Although I personally obtained a 23andme test a few years ago, I currently don’t recommend genetic testing to all of my patients, and I’m admittedly not an expert when it comes to interpreting the results of such tests. But I am continuously trying to expand my knowledge in this area, and as I mentioned earlier, I do think that such testing will become more routine in the future.
So hopefully you have a better understanding of phase one detoxification. It admittedly can be complex, and one of the big keys to optimizing phase one detoxification is to make sure you consume sufficient antioxidants to help offset the damage caused by the reactive intermediates. You also learned about how certain nutrients and herbs can induce and inhibit the phase one detoxification enzymes. And while the topic of genetic polymorphisms is complex, hopefully you realize that certain genetic defects of the phase one detoxification enzymes can affect the metabolism of different medications.