Biology:UGT2B7

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


UGT2B7 (UDP-Glucuronosyltransferase-2B7) is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain. In humans, UDP-Glucuronosyltransferase-2B7 is encoded by the UGT2B7 gene.[1][2]

Function

The UGTs serve a major role in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. UGT2B7 has unique specificity for 3,4-catechol estrogens and estriol, suggesting that it may play an important role in regulating the level and activity of these potent estrogen metabolites.

This enzyme is located on the endoplasmic reticulum and nuclear membranes of cells. Its function is to catalyse the conjugation of a wide variety of lipophilic aglycon substrates with glucuronic acid, using uridine diphosphate glucuronic acid.

Together with UGT2B4, UGT2B7 is capable of glucosidation of hyodesoxycholic acid in the liver, but, unlike the 2B4 isoform, 2B7 is also able to glucuronidate various steroid hormones (androsterone, epitestosterone) and fatty acids.[3][4] It is also able to conjugate major classes of drugs such as analgesics (morphine), carboxylic nonsteroidal anti-inflammatory drugs (ketoprofen), and anticarcinogens (all-trans retinoic acid).[4] UGT2B7 is the major enzyme isoform responsible for the metabolism of morphine, codeine, norcodeine and other opiates to their corresponding 3- and 6- glucuronides. For example, morphine metabolism produces morphine-3-glucuronide (M3G) which has no analgesic effect and morphine-6-glucuronide (M6G),[5] which has analgesic effects more potent than morphine.[6] As a consequence, altered UGT2B7 activity can significantly affect both the effectiveness and side-effects of morphine, as well as some related opiate drugs.[7][8][9][10][11]

Structure

Two protein domains (left, orange-yellow, and right, green-blue) dimerize to form UGT2B7. Both domains contain Rossmann-like folds, beta sheets (arrows) surrounded by alpha helices (spirals), which bind UDP-glucuronic acid.

No structure of a full human UGT enzyme has been determined yet, however Miley et al. resolved a partial UGT2B7 structure of the C-terminal portion showing two dimeric domains with Rossman-like folds in complex.[12][13] The Rossman fold typically binds nucleotide substrates, in this case the UDP-glucuronic acid cofactor involved in glucuronidation by UGT2B7. Generally, the C-terminus of UGT enzymes is highly conserved and binds the UDP-glucuronic acid cofactor, while the N-terminus (not resolved in this structure) is responsible for substrate binding.[14] This first resolved structure indicated that the C-terminus of one of the two dimers projected into the UDP-glucuronic acid binding site of the second dimer, thus rendering the second dimer ineffective.

Further studies have investigated dimerization of UGT enzyme polymorphisms and found both homodimer and heterodimer (with genetic polymorphisms of UGT2B7 or other UGT enzymes such as UGT1A1) formation are possible, with some combinations having an effect on enzyme activity.[15]

Genetic polymorphism

UGT2B7 is considered to be a highly polymorphic gene.[15] Various research efforts have investigated the potential effect of these polymorphic variants on glucuronidation activity of UGT2B7 and especially its clearance of administered drugs, including anticancer therapies. Decreased glucuronidation activity by genetically variant UGT2B7 could lead to increased toxicity due to elevated levels of the drug remaining or accumulating in a patient's organs especially liver, while increased activity could mean lower efficacy of the administered therapy due to lower than expected levels in the body.

One study found that Han Chinese dye-industry workers exposed to benzidine were at higher risk for developing bladder cancer if they had the UGT2B7 single nucleotide polymorphism (SNP) C802T encoding His268Tyr.[16] The histidine to tyrosine mutation at residue 268 is located in the N-terminal portion of UGT2B7, which binds the xenobiotic substrate as opposed to the C-terminus which binds UDP-glucuronic acid. The speculated mechanism for this increased cancer risk involved increased glucuronidation of benzidine by the mutant UGT2B7 followed by cleavage of the glucuronidated benzidine at urine pH levels, releasing higher concentrations of benzidine in the bladder. Another study looked for a similar association of variant UGT2B7 G900A with the risk of colorectal cancer but found no significant association.[17]

A study of erlotinib clearance in non-small cell lung cancer patients showed no statistical significance for SNPs of UGT2B7, which potentially metabolizes erlotinib as indicated by erlotinib inhibition of UGT2B7.[18] An investigation into the clearance of diclofenac, a nonsteroidal anti-inflammatory drug (NSAID) that can cause serious drug-induced liver injury, showed that mutant UGT2B7 with the C802T SNP had a 6-fold lower clearance of diclofenac than wild-type UGT2B7, possibly contributing to increased liver toxicity in patients with this mutation.[19] Analysis of genetic polymorphisms of UGT2B7 in anti-tuberculosis drug-induced liver injury (ATLI) found no association between mutations of UGT2B7 and ATLI in the studied population.[20]

UGT2B7 is also known to be involved in the metabolism of opioids via glucuronidation, and a study investigating the effect of polymorphisms on the analgesic efficacy of buprenorphine found that the mutation C802T significantly worsened the analgesic response to buprenorphine after thoracic surgery, particularly at longer time-points (48 hours) where this long-lasting opioid is meant to remain effective.[21] This same variant was found separately to have significant effects on the blood plasma concentration of valproic acid administered to epilepsy patients, which may account for some of the individual variability seen with this narrow-therapeutic window treatment.[22] Both of these cases indicate decreased concentrations of drug compound probably due to increased glucuronidation activity of UGT2B7 with the C802T polymorphism.

Summary of some of the recent published effects of the UGT2B7*2 (C802T) polymorphism.

Since UGT2B7 is involved in glucuronidation of many xenobiotic compounds, and polymorphisms of UGT2B7 are prevalent, investigation into potential effects of polymorphisms of UGT2B7 on clearance of pharmacologically relevant compounds is often of interest, as shown by the variety of studies undertaken. The UGT2B7 C802T polymorphism, for example, has been noted at 73% prevalence in Asians and 46% prevalence in Caucasians; therefore, effects of this polymorphism could impact a large portion of the population.[23] However, not all studies find significant changes in clearance due to these genetic polymorphisms. It is not always clear if this is due to the particular polymorphism not affecting enzyme activity of UGT2B7, or because the compound of interest is metabolized by various routes that can mask any differences due to changes in UGT2B7 activity.

References

  1. ↑ "Cloning and expression of human liver UDP-glucuronosyltransferase in COS-1 cells. 3,4-catechol estrogens and estriol as primary substrates". The Journal of Biological Chemistry 265 (14): 7900–6. May 1990. doi:10.1016/S0021-9258(19)39016-7. PMID 2159463. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=2159463. 
  2. ↑ "Isolation of a human YAC contig encompassing a cluster of UGT2 genes and its regional localization to chromosome 4q13". Genomics 23 (2): 496–9. September 1994. doi:10.1006/geno.1994.1531. PMID 7835904. 
  3. ↑ "Glucosidation of hyodeoxycholic acid by UDP-glucuronosyltransferase 2B7". Biochemical Pharmacology 65 (3): 417–21. February 2003. doi:10.1016/S0006-2952(02)01522-8. PMID 12527334. 
  4. ↑ 4.0 4.1 "Substrate specificity of the human UDP-glucuronosyltransferase UGT2B4 and UGT2B7. Identification of a critical aromatic amino acid residue at position 33". The FEBS Journal 274 (5): 1256–64. March 2007. doi:10.1111/j.1742-4658.2007.05670.x. PMID 17263731. 
  5. ↑ "Human UGT2B7 catalyzes morphine glucuronidation". Drug Metabolism and Disposition 25 (1): 1–4. January 1997. PMID 9010622. http://dmd.aspetjournals.org/cgi/content/abstract/25/1/1. 
  6. ↑ "Morphine-6-glucuronide: morphine's successor for postoperative pain relief?". Anesthesia and Analgesia 102 (6): 1789–97. June 2006. doi:10.1213/01.ane.0000217197.96784.c3. PMID 16717327. http://www.anesthesia-analgesia.org/cgi/content/full/102/6/1789. 
  7. ↑ "Role of active metabolites in the use of opioids". European Journal of Clinical Pharmacology 65 (2): 121–39. February 2009. doi:10.1007/s00228-008-0570-y. PMID 18958460. 
  8. ↑ "Association of UGT2B7 and ABCB1 genotypes with morphine-induced adverse drug reactions in Japanese patients with cancer". Cancer Chemotherapy and Pharmacology 65 (2): 251–8. January 2010. doi:10.1007/s00280-009-1029-2. PMID 19466410. 
  9. ↑ "Molecular cloning of the baboon UDP-glucuronosyltransferase 2B gene family and their activity in conjugating morphine". Drug Metabolism and Disposition 38 (4): 545–53. April 2010. doi:10.1124/dmd.109.030635. PMID 20071451. 
  10. ↑ "Considerations on the use of oxymorphone in geriatric patients". Expert Opinion on Drug Safety 8 (5): 603–13. September 2009. doi:10.1517/14740330903153854. PMID 19614559. 
  11. ↑ "Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine metabolism and relationship with the main UGT polymorphisms in a bank of human liver microsomes". Drug Metabolism and Disposition 38 (1): 40–5. January 2010. doi:10.1124/dmd.109.029546. PMID 19841060. 
  12. ↑ "Advances in the Understanding of Protein-Protein Interactions in Drug Metabolizing Enzymes through the Use of Biophysical Techniques". Frontiers in Pharmacology 8: 521. 2017. doi:10.3389/fphar.2017.00521. PMID 28848438. 
  13. ↑ "Crystal structure of the cofactor-binding domain of the human phase II drug-metabolism enzyme UDP-glucuronosyltransferase 2B7". Journal of Molecular Biology 369 (2): 498–511. June 2007. doi:10.1016/j.jmb.2007.03.066. PMID 17442341. 
  14. ↑ "Homo- and hetero-dimerization of human UDP-glucuronosyltransferase 2B7 (UGT2B7) wild type and its allelic variants affect zidovudine glucuronidation activity". Biochemical Pharmacology 95 (1): 58–70. May 2015. doi:10.1016/j.bcp.2015.03.002. PMID 25770680. 
  15. ↑ 15.0 15.1 "Inter-isoform Hetero-dimerization of Human UDP-Glucuronosyltransferases (UGTs) 1A1, 1A9, and 2B7 and Impacts on Glucuronidation Activity". Scientific Reports 6: 34450. November 2016. doi:10.1038/srep34450. PMID 27857056. Bibcode: 2016NatSR...634450Y. 
  16. ↑ "An association of UDP-glucuronosyltransferase 2B7 C802T (His268Tyr) polymorphism with bladder cancer in benzidine-exposed workers in China". Toxicological Sciences 85 (1): 502–6. May 2005. doi:10.1093/toxsci/kfi068. PMID 15615884. 
  17. ↑ "Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study". BMC Cancer 17 (1): 901. December 2017. doi:10.1186/s12885-017-3728-0. PMID 29282011. 
  18. ↑ "Population Pharmacokinetics and Adverse Events of Erlotinib in Japanese Patients with Non-small-cell Lung Cancer: Impact of Genetic Polymorphisms in Metabolizing Enzymes and Transporters". Biological & Pharmaceutical Bulletin 41 (1): 47–56. 2018-01-01. doi:10.1248/bpb.b17-00521. PMID 29311482. 
  19. ↑ "Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism". Toxicology Letters 284: 70–78. March 2018. doi:10.1016/j.toxlet.2017.11.038. PMID 29203276. 
  20. ↑ "Association of UGT2B7 polymorphisms with risk of induced liver injury by anti-tuberculosis drugs in Chinese Han". International Journal of Immunopathology and Pharmacology 30 (4): 434–438. December 2017. doi:10.1177/0394632017733638. PMID 28934901. 
  21. ↑ "Influence of uridine diphosphate-glucuronyltransferase 2B7 (UGT2B7) variants on postoperative buprenorphine analgesia". Pain Practice 15 (1): 22–30. January 2015. doi:10.1111/papr.12152. PMID 24256307. 
  22. ↑ "The influence of UGT2B7 genotype on valproic acid pharmacokinetics in Chinese epilepsy patients". Epilepsy Research 114: 78–80. August 2015. doi:10.1016/j.eplepsyres.2015.04.015. PMID 26088889. 
  23. ↑ "Prevalence of polymorphisms in the human UDP-glucuronosyltransferase 2B family: UGT2B4(D458E), UGT2B7(H268Y), and UGT2B15(D85Y)". Cancer Epidemiology, Biomarkers & Prevention 9 (3): 329–33. March 2000. PMID 10750673. 

Further reading

External links



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