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Analysis of substrate specificities and tissue expression of rat UDP-glucuronosyltransferases UGT1A7 and UGT1A8.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Webb, Laura J. Miles, Kristini K. Auyeung, Diana J. Kessler, Fay K. Ritter, Joseph K. |
| Copyright Year | 2005 |
| Abstract | The UGT1 complex codes for a subfamily of homologous "1A7-like" UDP-glucuronosyltransferases (UGTs), including UGT1A7 and UGT1A8. Little information is available regarding either the substrate specificities or regulation of the UGT1A7-like forms from rats. We compared the activities and tissue expression of UGT1A7 and UGT1A8, which exhibit 77% identity in their amino terminal sequence. UGT1A7 shows broad specificity, catalyzing the glucuronidation of 31 of 40 randomly selected substrates (100 muM) at rates >0.1 nmol/mg/min. UGT1A7 substrates included both planar and nonplanar compounds, mono- and polycyclic aromatics, and compounds with bulky side chain ring substitutions. UGT1A8 exhibited a narrower substrate specificity that completely overlapped with UGT1A7. UGT1A8 was most active toward the 1-OH, 4-OH, 5-OH, 6-OH, 7-OH, 10-OH, 11-OH, and 12-OH derivatives of benzo[a]pyrene. Other effective UGT1A8 substrates (>0.1 nmol/mg/min) included 9-OH-benzo[a]pyrene, 1-naphthol, 4-methylumbelliferone, 7-hydroxycoumarin, chrysin, quercetin, 4-nitrophenol, and estriol. In general, substrates preferred by UGT1A8 were polyaromatic planar structures with nonbulky substituents and a superimposable 1-naphtho ring structure. Studies of the tissue expression of the UGT1A7 and 1A8 mRNAs using RNase protection analysis suggested that each is expressed in liver and kidney of control rats. A major difference is the higher expression of UGT1A7 mRNA in intestine. These studies suggest complementary functions of the UGT1A7 and UGT1A8 forms in xenobiotic metabolism. Further studies are necessary to determine whether their relative contributions change as a function of development, hormonal status, or exposure to inducing agents. |
| Starting Page | 77 |
| Ending Page | 82 |
| Page Count | 6 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://dmd.aspetjournals.org/content/dmd/33/1/77.full.pdf |
| PubMed reference number | 15502008v1 |
| Volume Number | 33 |
| Issue Number | 1 |
| Journal | Drug metabolism and disposition: the biological fate of chemicals |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 1-naphthol 4-nitrophenol 7-hydroxycoumarin Benzo(a)pyrene Estriol Hymecromone Intestinal Wall Tissue Intestines Milligram per Minute Millimole per Kilogram Polycyclic Hydrocarbons, Aromatic Quercetin Renal Tissue Subfamily Substrate Specificity UDP-Glucuronosyltransferase 1-7 UDP-glucuronosyltransferase, UGT1A8 UGT1A7 gene Uridine Diphosphate chrysin |
| Content Type | Text |
| Resource Type | Article |
