Disease relevance of UGT1A9

• Insect cells were co-infected with baculoviruses encoding both HA-tagged and His-tagged UGT1A9 [1].
• Whereas UGT1A9 was not regulated, differential regulation of UGT1A7 and UGT1A10 mRNA was observed between normal oesophageal epithelium and squamous-cell carcinoma [2].
• In addition, the UGT1A9 -118 (dT)(9/9) genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047) [3].
• PURPOSE: To determine whether uridine diphosphate-glucuronosyltransferase 1A1, UGT1A7, and UGT1A9 polymorphisms affect the pharmacokinetics (PK) of irinotecan and treatment outcome of Korean patients with advanced non-small-cell lung cancer (NSCLC) [4].
• BACKGROUND & AIMS: Approximately 13% of patients with chronic hepatitis D virus (HDV) infection have liver-kidney microsomal antibodies type 3 (LKM-3) directed against family 1 uridine 5'-diphosphate-glucuronosyl-transferases (UGT-1) [5].

High impact information on UGT1A9

• METHODS: Genomic DNA from the blood of 59 patients with hepatocellular carcinoma and 70 control subjects without evidence of cancer was analyzed by UGT1A7- and UGT1A9-specific PCR, sequencing analysis, and temperature gradient gel electrophoresis [6].
• This study examines the association of UGT1A7 and UGT1A9 gene polymorphisms with hepatocellular carcinoma [6].
• Characterization of common UGT1A8, UGT1A9, and UGT2B7 variants with different capacities to inactivate mutagenic 4-hydroxylated metabolites of estradiol and estrone [7].
• Furthermore, a >12-fold decreased intrinsic clearance of the *1 proteins was induced by selected amino acid substitutions in UGT1A8 (*3 C277Y) and UGT1A9 (*3 M33T) [7].
• UGT1A9 was identified as the isozyme catalyzing biotransformation of the two compounds in HT29 cells and propofol as an effective competitive inhibitor of this metabolism [8].

Chemical compound and disease context of UGT1A9

• CONCLUSIONS: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan [3].

Biological context of UGT1A9

• (2) In vitro immunoinhibition experiments showed that glucuronidation of the anticancer drug flavopiridol by UGT1A1 was more strongly inhibited than its UGT1A9-mediated biotransformation [9].
• CYP1A2 generated 2AAF- and PhIP-mediated DNA damage, but only the action of N-hydroxy-2AAF was blocked by expressed UGT1A9 [10].
• A novel nonsynonymous single nucleotide polymorphism was identified in UGT1A9 exon 1, heterozygous 766G>A resulting in the amino acid substitution of D256N [11].
• Although several genetic polymorphisms are reported for UGT1A1 and UGT1A7 that affect the SN-38 glucuronidation activities, no such polymorphisms have been identified for UGT1A9 [11].
• The relationships of the exons 1 to each other are as follows: UGT1A2p through UGT1A5 comprises a cluster A that is 87-92% identical, and UGT1A7 through UGT1A13p comprises a cluster B that is 67-91% identical [12].

Anatomical context of UGT1A9

• Membranes from the co-infected cells, or a mixture of membranes from separately infected cells, were subjected to detergent extraction and IMAC, and the resulting fractions were analyzed for the presence of each type of UGT1A9 using tag-specific antibodies [1].
• In support of the involvement of UGT1A9, a strong coefficient of correlation was observed in the glucuronidation of SN-38 and a substrate, mainly glucuronidate, by UGT1A9 (flavopiridol) by human liver microsomes (coefficient of correlation, 0.905; p = 0.002) [13].
• Treatment of human hepatocytes and macrophages and murine adipocytes with activators of PPAR alpha or PPAR gamma resulted in an enhanced UGT1A9 expression and activity [14].
• UGT1A8 and 1A10 are expressed exclusively in the gastrointestinal tract, whereas UGT1A9 is expressed mainly in the liver and kidneys [15].
• Microsomes expressing UGT1A9 produced N-hydroxy-PhIP-N3-glucuronide at the highest rate with an apparent Km and Vmax of 3.73 microM and 4.07 pmol/min/mg, respectively [16].

Associations of UGT1A9 with chemical compounds

• Purified UGT1A9 glucuronidated scopoletin at a high rate, whereas its glucuronidation activity toward entacapone was low and largely dependent on phospholipid addition [1].
• In the case of UGT1A9, however, glucuronidation of alpha-naphthol and scopoletin was resistant to such inhibition, whereas glucuronidation of entacapone and several other aglycones was sensitive [1].
• When co-infected with His-tagged UGT1A9, however, part of the HA-tagged enzyme was bound to the column and was eluted by imidazole concentration gradient together with the His-tagged UGT1A9, suggesting the formation of stable dimers that contain one His-tagged and one HA-tagged UGT1A9 monomers [1].
• Entacapone in particular was seen to be an exceptionally good substrate for UGT1A9 with an even higher reaction velocity value at 500 microM substrate concentration compared with that of the commonly used substrate, propofol (1.3 and 0.78 nmol min(-1) mg(-1), respectively) [17].
• Nicotine and cotinine N-glucuronidations in pooled human liver microsomes were competitively inhibited by bilirubin as a substrate for UGT1A1 (K(i) = 3.9 and 3.3 micro M), imipramine as a substrate for UGT1A4 (K(i) = 6.1 and 2.7 micro M), and propofol as a substrate for UGT1A9 (K(i) = 6.0 and 12.0 micro M) [18].

Enzymatic interactions of UGT1A9

• Valproic acid inhibited UGT1A9 catalyzed propofol glucuronidation in an uncompetitive manner and UGT2B7 catalyzed AZT glucuronidation competitively (K(i)=1.6+/-0.06mM) [19].

Regulatory relationships of UGT1A9

• Vmax for 1A9 was fourfold higher than that measured for UGT2B7, 92 compared with 21 pmol min(-1) mg(-1), respectively, but UGT1A9 was expressed at approximately twofold higher level than the UGT2B7 in the recombinant cell lines [20].
• Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism [21].

Other interactions of UGT1A9

• In addition, both UGT1A9 and UGT1A7 preferentially formed BPD-7R-Gluc [22].
• Significantly lower expression of UGT1A9 and UGT2B4 mRNA was identified in paediatric liver [23].
• Evidence for at least two PAH-inducible UGTs (UGT1A6 and UGT1A9) is presented, which, however, are also constitutively expressed in a tissue- and cell-specific manner [24].
• These results imply that concomitant chronic intake of therapeutic drugs and dietary components that are UGT2B7 and/or UGT1A9 substrates may interfere with estragole metabolism [25].
• The inhibitory effects of propofol as a specific substrate for UGT1A9 (IC(50) = 167.1 microM) and emodin as a substrate for UGT1A8 and UGT1A10 (IC(50) = 287.6 microM) were not prominent [26].

Analytical, diagnostic and therapeutic context of UGT1A9

• Furthermore, an HNF4alpha response element (HNF4alpha RE) was identified in the promoter of human UGT1A9 at position -372 to -360 base pairs by transient transfection, electrophoretic mobility shift assays, and chromatin immunoprecipitation experiments [27].
• The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients [28].
• RT-PCR analysis demonstrate that UGT1A9 transcript is expressed in several tissues, which include the prostate, testis, breast, ovary, and skin of the monkey and humans [29].
• Despite limitations resulting from sample size, results indicate that UGT1A9 I399 and -118T(9/10) may represent additional candidates in combination with UGT1A1 promoter haplotypes for the prediction of SN-38 glucuronidation profile in vivo [30].
• The enzyme activity of CHL-UGT1A9 towards propranolol in S9 protein of the cell was determined by HPLC [31].

References