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-catecholestrogens and estriol, suggesting that it may play an important role in regulating the level and activity of these potent estrogen metabolites.
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-transretinoic acid).[4] UGT2B7 is the major enzyme isoform for the metabolism of morphine to the main metabolites, 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
File:UGT2B7 rossmann folds.pngTwo 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 UGT27B, 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.
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.
↑Monaghan G, Clarke DJ, Povey S, See CG, Boxer M, Burchell B (September 1994). "Isolation of a human YAC contig encompassing a cluster of UGT2 genes and its regional localization to chromosome 4q13". Genomics. 23 (2): 496–9. doi:10.1006/geno.1994.1531. PMID7835904.
↑Mackenzie P, Little JM, Radominska-Pandya A (February 2003). "Glucosidation of hyodeoxycholic acid by UDP-glucuronosyltransferase 2B7". Biochemical Pharmacology. 65 (3): 417–21. doi:10.1016/S0006-2952(02)01522-8. PMID12527334.
↑ 4.04.1Barre L, Fournel-Gigleux S, Finel M, Netter P, Magdalou J, Ouzzine M (March 2007). "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. doi:10.1111/j.1742-4658.2007.05670.x. PMID17263731.
↑Coller JK, Christrup LL, Somogyi AA (February 2009). "Role of active metabolites in the use of opioids". European Journal of Clinical Pharmacology. 65 (2): 121–39. doi:10.1007/s00228-008-0570-y. PMID18958460.
↑Fujita K, Ando Y, Yamamoto W, Miya T, Endo H, Sunakawa Y, Araki K, Kodama K, Nagashima F, Ichikawa W, Narabayashi M, Akiyama Y, Kawara K, Shiomi M, Ogata H, Iwasa H, Okazaki Y, Hirose T, Sasaki Y (January 2010). "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. doi:10.1007/s00280-009-1029-2. PMID19466410.
↑Pergolizzi JV, Raffa RB, Gould E (September 2009). "Considerations on the use of oxymorphone in geriatric patients". Expert Opinion on Drug Safety. 8 (5): 603–13. doi:10.1517/14740330903153854. PMID19614559.
↑Rouguieg K, Picard N, Sauvage FL, Gaulier JM, Marquet P (January 2010). "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. doi:10.1124/dmd.109.029546. PMID19841060.
↑Yuan L, Qian S, Xiao Y, Sun H, Zeng S (May 2015). "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. doi:10.1016/j.bcp.2015.03.002. PMID25770680.
↑Sun YX, Zhuo WY, Lin H, Peng ZK, Wang HM, Huang HW, Luo YH, Tang FQ (August 2015). "The influence of UGT2B7 genotype on valproic acid pharmacokinetics in Chinese epilepsy patients". Epilepsy Research. 114: 78–80. doi:10.1016/j.eplepsyres.2015.04.015. PMID26088889.
↑Lampe JW, Bigler J, Bush AC, Potter JD (March 2000). "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. PMID10750673.
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