SNP Highlight - UGTs and Detox

The Role of Detoxification in the Body

The detoxification system of the body is a series of biological pathways designed to metabolize, reduce, and eliminate potentially hazardous compounds including environmental toxins, drugs, xenobiotics, and steroid hormones from the body.

This system consists of three phases, bioactivation, conjugation, and transport or elimination. Phase I detoxification occurs in the liver and consists of chemical reactions (oxidation, reduction, hydrolysis, hydration, or dehalogenation) that add a reactive group (hydroxyl, carboxyl, or an amino group) to a toxin to create a hydrophilic molecule. Phase I reactions are primarily catalyzed by a group of enzymes that belong to the cytochrome P450 family. This reaction generates a reactive molecule that can readily bind to other molecules, such as DNA and proteins. The reactive intermediate substances that are created in phase I are considered more toxic than the original compound and need to be reduced by phase II enzymes as quickly as possible to avoid an overaccumulation of free radicals and toxins in the body. 

Phase II of the detoxification pathway also occurs primarily in the liver and uses conjugation reactions to convert the reactive molecules generated in phase I into water-soluble, non-toxic molecules that can be eliminated from the body through the urine or bile (phase III). This process of conjugation requires energy in the form of adenosine triphosphate (ATP) and a water-soluble moiety to attach to the reactive toxin. The phase II enzymes, which carry out this process of conjugation, consist of many enzyme super-families including superoxide dismutase (SODs), glutathione S-transferases (GSTs), sulfotransferases (SULTs), UDP-glucuronosyltransferases (UGTs), glutathione S-transferases (GSTs), and N-acetyltransferases (NATs).

The Genetics of Detoxification

Each phase of the detoxification system is highly dependent on well-controlled enzyme activity. SNPs in the genes coding for various enzymes in the detoxification pathway can alter enzyme activity. Both increased and decreased enzyme activity in phase I enzymes can result in adverse consequences if there is not adequate support and clearance in phase II enzymes. This imbalance can lead to the over-accumulation of toxic intermediates that may be more harmful than the original compounds. 

Additionally, normal phase I activity with decreased phase II enzyme activity results in an increase in these toxic intermediate molecules with decreased clearance. It also prolongs the systematic exposure of the body resulting in potentially harmful consequences.

The Role of UDP-glucuronosyltransferases (UGTs) in Phase II Detoxification

Phase II glucuronidation is catalyzed by the superfamily of enzymes, UDP-glucuronosyltransferases (UGTs), and is an important pathway through which endogenous and exogenous lipophilic compounds are modified to a more polar, less reactive compound that catalyze the covalent addition of glucuronic acid to a wide range of lipophilic chemicals. Research suggests that 40% to 70% of all medications are subject to glucuronidation reactions in humans, thus highlighting the significance of this conjugation enzyme family (1).

The Impact of UGT1A1 Variants on Enzyme Activity

The UGT1A1 isoform, which is expressed mainly in the liver and GI tract (2), is primarily responsible for the glucuronidation of bilirubin in the human liver as well as the conjugation of phenols, flavonoids, anthraquinones, and various drugs (3; 4; 5). Additionally, bilirubin is hypothesized to be a cellular antioxidant in the human body which may further deplete the body’s ability to accommodate phase I reactions (6).

Individuals with variants in the UGT1A1 isoforms have been shown to have reduced transcriptional activity or significantly reduce enzyme activity, both resulting in impaired phase II conjugation reactions (7; 8; 9). 

Among the numerous SNPs of UGT1A1, UGT1A1*6 (rs4148323), UGT1A1*60 (rs4124874), and UGT1A1*93 (rs10929302) are known as core markers of UGT1A1 (10). These functional polymorphisms in UGT1A1 are associated with altered UGT enzyme function and reduced bilirubin glucuronidation activity resulting in elevated levels of bilirubin, which is linked with conditions such as cardiovascular disease, diabetes, impaired drug metabolism, and Gilbert’s syndrome (11; 12). However, these variants are not distributed evenly among all populations. In fact, the UGT1A1*60 (rs4124874) is the most prevalent across all ethnicities except for individuals of African descent (13), while the UGT1A1*6 (rs4148323) is expressed at a disproportionate rate in Asians (14), and UGT1A1*93 (rs10929302) is highly expressed in Africans (15). Studies suggest that individuals who carry at least one variant allele in the core markers of UGT1A1 can have up to a 30% reduction in enzyme activity (16). 

Nutritional Support for UGT1A1 Enzyme Activity

Both clinical and observational studies strongly indicate that consuming a diet rich in cruciferous vegetables (5 to 10 servings per day) can significantly improve UGT enzyme activity (17; 18). This effect has been mainly attributed to the compound found within cruciferous foods, 3,3'-Diindolylmethane (DIM) (19). 

Research also points to the compound resveratrol, found in foods such as grapes, red wine, peanuts, nuts, blueberries, strawberries, and dark chocolate as a potentially effective modulator of UGT1A1 enzyme activity (20).

Additionally, in vivo studies suggest other compounds found in a healthy diet including ellagic acid, ferulic acid, and astaxanthin may help to support UGT enzyme activity (21). And supplementing with the anti-inflammatory compound curcumin may benefit those individuals with impaired UGT activity (22).