Phase 2 Detoxification – UGTs

This is part of an ongoing series on the genes involved in detoxification.

UDP-glucuronosyltransferase (abbreviated UGT) creates a glucuronidation reaction, which is a big part of Phase II detoxification.  Once a drug, toxin, or other substance is broken down in a Phase I reaction (see the CYP genes), the Phase II reactions further alter the substance so that it can be excreted from the body.

The reaction catalyzed by the UGT enzyme involves the addition of a glucuronic acid moiety to xenobiotics and is the most important pathway for the human body’s elimination of the top 200 drugs. It is also the major pathway for foreign chemical (dietary, environmental, pharmaceutical) removal for most drugs, dietary substances, toxins and endogenous substances.  – Wikipedia

There are quite a few genes involved in glucuronidation, and most are prefixed with UGT.

 

UGT1A1 is involved in the breakdown of bilirubin, estrogen, and several carcinogens. Gilbert’s Syndrome is associated with this gene and involves bilirubin not being broken down appropriately.  One study in 2009 showed that the levels of UGT1A1 activity can be increased with cruciferous vegetables.  This may be one way that cruciferous veggies are protective against cancer.

Bilirubin, a substance that brings to mind jaundice in babies, is a breakdown product naturally caused in a body as it clears out aged red blood cells.  It is excreted in bile and urine, and gives feces its brown color.

UGT1A1 is also responsible for the breakdown of BPA (in plastics) [ref].

There are a couple of SNPs that are supposed to code for higher bilirubin and lower activity in UGT1A1 known as *28. UGT1A1*28 is significant for those undergoing irinotecan treatment for colon cancer.  I’m unclear right now as to what each SNP means since I’m seeing conflicting information.  You can look at the information on SNPedia for rs34815109 which gives an explanation, and then look at rs34983651 and rs35600288. PharmGKB also lists several articles showing that rs8175347 (not in 23andMe) is associated with UGT1A1*28, as well as rs6742078 (see below).

 

Check your 23andMe results for rs4148323:

  • AA: UGT1A1*6 – increased bilirubin level, Gilbert’s syndrome in Asian populations
  • AG: Carrier of UGT1A1*6
  • GG: normal

 

Check your 23andMe results for rs4124874:

  •  GG: UGT1A1*60[ref], reduced activity, increased bilirubin (Caucasian)[ref]
  •  TT: normal

 

Check your 23andMe results for rs6742078:

  •  TT: increased bilirubin levels, increased gallstone risk (males)[ref]
  •  GG: normal

 UGT1A6 is also involved in transforming bilirubin, hormones, and certain drugs (aspirin, acetaminophen)  into water-soluble metabolites that can then be excreted from the body.  Studies on this gene also look at the polymorphisms in association with benzene poisoning.

 

Check your 23andMe results for rs887829:

  •  TT: higher serum bilirubin levels, protective against heart disease
  •  CC: normal

 

Check your 23andMe results for rs17863783:

  •  T-allele: protective against bladder cancer
  • GG: normal

 

UGT1A9 polymorphisms:   There is not a lot of information was available for this gene, so it is something to come back to in the future.  UGT1A9*3 is thought to be a non-functioning version, but the SNP (rs72551330) isn’t available in 23andMe data.  [ref]

Check your 23andMe results for rs6714486:

  • AA: higher activity [ref] [ref]
  • TT: normal

 

 

More to read:
UGT1a1 polymorphisms are important determinants of dietary carcinogen detoxification in the liver (2005)

Regulation of the UGT1a1 Bilirubin-Conjugating Pathway (2006)

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