Shedding Light On Detox

How Genes Influence Your Detox Pathways

Detoxification is defined as: the process of removing toxic substances or qualities. 

Historically this word was primarily used to refer to medical procedures designed to rid the body of toxic substances. Now it has become a buzzword attached to a plethora of supplements and health products. 

Detoxification is a critical process within the body that has a significant impact on human health (1). The role of detoxification in health and wellness is especially important in today’s polluted world. The EPA estimates that humans could be exposed to up to 84,000 different man-made chemical compounds that are pervasive in our environment (2). Exposure to these chemicals occurs via the air we breathe, medications we take, cleaning products we use, personal care products we put on our skin, and nearly every other man-made product we come into contact with on a daily basis.                                                                                                                                                             

When we come into contact with and absorb or ingest these toxic compounds, our body has to neutralize and eliminate them and it does this via a 3 phase process (3). 

Phase I is the initial transformation phase. This phase takes place mainly in the liver and involves the oxidation, reduction or hydrolysis of fat soluble compounds into water soluble compounds that are often more toxic and unstable than the original toxin. 

Phase II is the conjugation phase. This phase also takes place primarily in the liver where Phase I metabolites are converted into more water soluble, less toxic compounds via acetylation, glucuronidation, glutathionylation, methylation, or sulfation.

Phase III is the excretion phase. It takes place primarily in the liver, kidneys or intestines and involves the transportation of these conjugated compounds out of cells and out of the body. 

There is a distinct set of enzymes required to carry out each of these 3 phases of detoxification. The activity of these enzymes is largely influenced by genetic factors. In this article we are going to discuss genetic polymorphisms that influence detoxification enzymes and their significance to human health. 

Phase I Detox - Cytochrome P450 Enzymes 

Phase I detoxification is carried out primarily through the cytochrome P450 enzymes (CYP). There are dozens of genes and hundreds of single nucleotide polymorphisms (SNPs) that impact the activity of these enzymes. We will focus on a select few of the genes. 

CYP1A2 is important for the metabolism of polycyclic aromatic hydrocarbons (PAHs), caffeine, estrogen, aflatoxin B1, and acetaminophen. Variations in this gene and the activity of the CYP1A2 enzyme have shown to be protective against heart disease and breast cancer, particularly in the presence of high caffeine consumption (4, 5, 6). Those with high CYP1A2 activity metabolize the aforementioned toxins rapidly and appear to be protected from many of the negative effects of increased exposure to these compounds. 

CYP1B1 has particular importance for the metabolism of estrogen in various tissues. Several studies have shown that polymorphisms in this gene are related to the development of hormone driven cancers including endometrial, breast, and prostate cancer (7). 

CYP2A6 is responsible for approximately 75% of total nicotine metabolism along with the metabolism of coumarin, aflatoxin B1, nitrosamines, and some medications.  Several studies have shown that individuals with polymorphisms that increase the activity of the CYP2A6 enzyme tend to smoke more and have a higher risk of lung cancer even after adjustment for the number of cigarettes smoked per day (8). Variations in this gene are also associated with high rates of oral, pharynx, larynx, and esophageal cancers (9). 

CYP2C9 is involved with the metabolism of a large number of medications including NSAIDs, warfarin, and tamoxifen. Previous research has focused on the impact of variations in this gene on warfarin and NSAIDS. Studies have shown that this gene can impact warfarin clearance and warfarin dosing requirements (10). There is also a greater risk for GI bleeding in response to NSAID use among individuals with SNPs in this gene (11). 

Cofactors of Phase 1 Detox 

Genetics can also influence phase I detox pathways indirectly through their impact on nutrients that serve as cofactors for phase I enzymes. These nutrients include b-vitamins, vitamin E, vitamin C, carotenoids, and various other antioxidants (12). Hundreds of additional genes can influence the status of these nutrient cofactors. 

Phase II Detox 

Unlike phase I detox, which is carried out through one family of enzymes (CYP), phase II detox has several distinct sets of enzymes that perform very specific functions. Sulfation reactions are carried out by sulfurtransferase enzymes, glutathione transferase enzymes carry out glutathionylation, UDP-Glucuronosyltransferase carry out glucuronidation, N-Acetyltransferases carry out acetylation, and methyltransferases carry out methylation. 

Sulfurtransferases are a family of phase 2 enzymes that add sulfur groups to compounds in order to make them more water soluble and less reactive. The sulfation pathway is used to detoxify a variety of endobiotics and xenobiotics including phenols, amines, steroid hormones, neurotransmitters, various drugs, and food dyes (13). Alterations in this pathway have been associated with altered enzyme function and increased risk of total, upper respiratory, and hepatic cancers (13, 14, 15).

Primary Gene: SULT1A1

Glutathione transferases are a family of phase 2 enzymes that catalyze 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. GSTs play a major role in the detoxification of polycyclic aromatic hydrocarbons (PAHs), prostaglandins, steroids, pesticides, herbicides, mycotoxins, air pollutants, cigarette smoke, heavy metals and pharmaceutical drugs (16, 17). Variations in this family of genes has been associated with rates of several types of cancer, allergies, Alzheimer’s, Autism, peripheral neuropathy, type 2 diabetes, high blood pressure, and cataracts (17). 

Primary Genes: GSS, GSTA1, GSTA2, GSTM1, GSTM3, GSTM5, GSTP

UDP-Glucuronosyltransferases (UGT) are another group of phase 2 enzymes that are responsible for the glucuronidation of toxic compounds to be excreted by the kidneys. Approximately 40–70% of all pharmaceuticals are metabolized by UGTs along with PAHs, estrogen, thyroid hormones, nitrosamines, BPA, HACs, and mycotoxins (18). Polymorphisms in the UGT genes are associated with risk for bladder, breast, colorectal, endometrial, esophageal, head and neck, liver, lung, prostate, and thyroid cancers (19). 

Primary Genes: UGT1A1, UGT1A6 

N-Acetyltransferases are phase II enzymes that are responsible for acetylation of many aromatic amines, and a number of compounds found in pharmaceutical drugs (21). Polymorphisms in these genes are associated with urinary, bladder, and breast cancers insulin resistance, heart disease, Alzheimer’s and Parkinson’s disease (21, 22, 23).

Genes: NAT1 and NAT2

Methyltransferases are phase II enzymes responsible for methylation reactions. COMT is the most well-studied gene in the methyltransferase family. It is responsible for the detoxification of catecholamine transmitters (norepinephrine, epinephrine, and dopamine). By regulating the breakdown of these neurotransmitters COMT is an important factor in mood, behavior, cognition, pain tolerance, and cardiovascular disease (24). COMT also helps with the breakdown of drugs with catechol structure. 

Primary Gene: COMT 

Phase III detox 

Phase III detox is the excretion phase of detoxification which is regulated primarily through genes in the ATP binding cassette protein (ABC) and the solute carrier (SLC10) families. These phase III enzymes are expressed throughout the body in tissues such as the liver, intestine, kidney, and brain, and they play crucial roles in the absorption, distribution, and excretion of lipids, several drugs, and environmental toxins.  

The ABC family of enzymes includes 49 different genes and 7 subfamilies of genes (ABCA, ABCB, ABCC, ABCD, ABCE, ABCF, ABCG). Notable enzymes include P-glycoprotein, multidrug resistance-associated proteins, and organic anion transporting polypeptide-2. These genes primarily influence the absorption and efflux of drug metabolites into and out of cells (25). 

The SLC10 family of genes includes 7 genes in total, but only two genes that are involved in phase III detoxification. SLC10A1 and SLC10A2 are involved in the production, absorption, and excretion of bile salts, which is a primary source of excretion of phase II metabolites out of the body through the small intestine (26). 

Conclusion

Detoxification is a complex process that is under the influence of hundreds of genes and thousands of SNPs. Genetic testing can provide important insight into our ability to effectively clear toxins from the body and reduce the potentially harmful effects of these various compounds that are pervasive throughout our environment.

As we continue to increase the volume and variety of toxins that we are exposed to on a daily basis, it is important that we gain a more thorough understanding of the process of detoxification and the genetic factors that drive detox capabilities.

Visit our website to learn more about Toolbox Genomics Detox panel!

For more on empowering your clients to become directly involved in their own DNA and epigenetic insights, don't forget to check out our sister site, MyToolboxGenomics.com.