Welcome back to the GPL-BLOG. Over the past several weeks we’ve been discussing a lot of the environmental toxins that everyone is exposed to on a daily basis. These toxins must be processed and detoxified. Most of this is done in the liver through several different processes that include Cytochrome P450 (P450) biotransformation, glutathione conjugation, enzyme hydrolyzing, sulfation, and glucuronidation.
Detoxification is often referred to as a two stage process (phase 1 and phase 2) of metabolism (Figure 1). Phase 1 metabolism involves the reduction or hydrolysis of the compound (usually caused by the addition of an oxygen molecule). The addition of oxygen to a compound is referred to as oxidation. This process is usually performed by the P450 enzymes.
The P450s are a family of enzymes that are found in numerous tissues throughout the body. However, a majority of these are found in the liver. The P450s are important for the detoxification of many foreign substances, including environmental toxicants and medications. The P450s are also important in controlling the levels of different molecules produced in the body such as the synthesis and breakdown of hormones, steroids, and multiple other molecules.
In humans, 58 different P450s have been discovered. However, only a subset of these is involved in the degradation of xenobiotics (chemicals that come from outside the body). These enzymes have different substrates, which are determined by the activity pocket of each enzyme. In regards to detoxification the most important P450s are Cyp1A2, Cyp2A6, Cyp2C9, Cyp2C19, Cyp2D6, Cyp2E1, and Cyp3A4. Besides detoxification, these enzymes metabolize a majority of medications (figure 2).
Here are some important detoxification enzymes:
Cyp1A2 is important for the metabolism of polycyclic aromatic hydrocarbons (PAHs), which are found in cigarette smoke. Other substrates include medications, aflatoxin B1, caffeine, and acetaminophen. The major polymorphism is Cyp1A2*1K, which results in a decrease of activity.
Cyp2A6 is involved in the metabolism of nicotine. Cyp2A6 is also involved in the metabolism of medications. The major polymorphic alleles are Cyp2A6*4 and Cyp2A6*9 (which can have between 35% -70% activity depending on if you have one or two polymorphic copies).
Cyp2C9 is involved with the metabolism of a large number of medications including NSAIDs, warfarin, and tamoxifen. There are multiple polymorphisms that affect activity of the enzyme.
Cyp2C19 is involved with the metabolism of multiple medications. The most common are diazepam, omeprazole, and sertraline. Cyp2c19 also metabolizes progesterone. There are two major variants that result in loss of activity. These are Cyp2C19*2 and Cyp2C19*3.
Cyp2D6 is involved with the metabolism of about 20% of drugs on the market. It also metabolizes serotonin and neurosteroids. There are five different polymorphisms that can lead to decreased activity. Some of the classes of drugs that are metabolized by Cyp2D6 are antidepressants, SSRIs, opioids, and antipsychotics.
Cyp2E1 is involved with the detoxification of many industrial pollutants, as well as carcinogens. Cyp2e1 also metabolizes ethanol to acetaldehyde and acetate. Cyp2e1 is also responsible for bioactivating a number of carcinogens, including cigarette smoke.
Cyp3A4 is responsible for metabolizing more compounds than most other P450s. It is responsible for metabolizing sex hormones, caffeine, statins, SSRIs, antifungals, antidepressants, and many other medications. Some antibiotics can negatively affect its activity. Also, grapefruit and pomegranate juice have been shown to be potent inhibitors.
Sulfur transferase is a phase 2 enzyme that adds sulfur groups to compounds in order to make them more water soluble and less reactive. This process is used on a wide variety of toxic molecules including phenols, amines, acetaminophen, and food dyes. Many chemicals that are able to become airborne are sulfated. Patients with autism have been found to have impaired sulfation ability, which will make these individuals more sensitive to toxins.
Glutathione transferase is a phase 2 enzyme that catalyzes the conjugation of glutathione to substrates. The addition of glutathione to toxins prevents these compounds from interacting with proteins in the body and allows them to be excreted via urine or bile. There are a wide variety of compounds that are conjugated with glutathione. A partial list includes pesticides, herbicides, carcinogens, acetaminophen, and mycotoxins.
Glucuronosyltransferase (UGT) is another phase 2 enzyme that is responsible for the glucuronidation of many different toxic chemicals. This process involves the addition of a glucuronosyl group to substrate molecules making them more polar and more easily excreted by the kidneys.
Paraoxonase 1 (PON1) is an enzyme that is able to perform paraoxonase activity on substrates. This enzyme is able to hydroylse and detoxify many different types of organophophate molecules. PON1 is one of the major pathways that protects people from these types of compounds. Mutations to PON1 could lead someone to be more sensitive to pesticides. Infants do not have a lot of PON1 activity. PON1 becomes active between birth and seven years of age.
These are the major pathways that you should be aware of when you are thinking about detoxification. Please see Table 1 to help you understand which pathway is mostly responsible for detoxifying these common toxicants. Also see Figure 1 to help you understand what you can do to help support type 1 and type 2 detoxification pathways. Detoxification of compounds by glutathione can be assisted by the supplementation of additional glutathione. Next week I will discuss some additional methods to help with detoxification.
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