CHARACTERIZATION OF RABBIT UDP-GLUCURONOSYLTRANSFERASE UGT1A7 - TERTIARY AMINE GLUCURONIDATION IS CATALYZED BY UGT1A7 AND UGT1A4 (VOL 344, PG 357, 1997)

A rabbit liver UDP-glucuronosyltransferase cDNA that is related to hum an and rat UGT1A7 has been identified. The predicted amino acid sequen ce of the UGT1A71 displays 80% similarity to that encoded by human HP4 (UGT1A9), but 81% to that predicted for human UGT1A7 and 77% to the r at UGT1A7 (UGTA2). The exons encoding human UGT1A7 and rat UGTA2 are t he seventh of the series of cassette exons that flank the 3' common ex on series of the UGT1A locus. Southern blot analysis demonstrates that the exon sequence encoding UGT1A71 is part of a larger cluster of hig hly related genes, The UGT1A71 RNA is expressed in both neonatal and a dult liver, and unlike rat UGT1A2 which is inducible with Ah receptor ligands such as polycyclic aromatic hydrocarbons, rabbit UGT1A7 is not regulated when animals are exposed to these inducers. Following expre ssion of UGT1A71 in COS-l cells, glucuronidation activity was identifi ed for small phenolic molecules like 4-nitrophenyl, bulky phenols as r epresented by 4-hydroxybiphenol and octylgallate, as well as 4-hydroxy estrone. In addition, UGT1A71 possesses catalytic activity toward tert iary amines like the tricyclic antidepressant imipramine. The pattern of UGT1A71 glucuronidation is similar to that observed for human UGT1A 9, except tertiary amines are not subject to glucuronidation by human UGT1A9. Glucuronidation of tertiary amines is catalyzed principally by human UGT1A4 as well as rabbit UGT1A4. Although rabbit UGT1A7 catalyz es the formation of quarternary ammonium glucuronides, the V-max is co nsiderably less than that observed for rabbit UGT1A4. Overall, the cha racterization of rabbit UGT1A7 suggests that this protein represents t he ortholog of the human UGT1A7, which to date has not been identified . (C) 1997 Academic Press.