Characterization of Rabbit UDP-Glucuronosyltransferase UGT1A7: Tertiary Amine Glucuronidation Is Catalyzed by UGT1A7 and UGT1A4 (original) (raw)

1997, Archives of Biochemistry and Biophysics

phenols as represented by 4-hydroxybiphenol and octylgallate, as well as 4-hydroxyestrone. In addition, A rabbit liver UDP-glucuronosyltransferase cDNA UGT1A7l possesses catalytic activity toward tertiary that is related to human and rat UGT1A7 has been amines like the tricyclic antidepressant imipramine. identified. The predicted amino acid sequence of the The pattern of UGT1A7l glucuronidation is similar to UGT1A7l displays 80% similarity to that encoded by that observed for human UGT1A9, except tertiary human HP4 (UGT1A9), but 81% to that predicted for amines are not subject to glucuronidation by human human UGT1A7 and 77% to the rat UGT1A7 (UGTA2). UGT1A9. Glucuronidation of tertiary amines is cata-The exons encoding human UGT1A7 and rat UGTA2 lyzed principally by human UGT1A4 as well as rabbit are the seventh of the series of cassette exons that UGT1A4. Although rabbit UGT1A7l catalyzes the flank the 3 common exon series of the UGT1A locus. formation of quarternary ammonium glucuronides, Southern blot analysis demonstrates that the exon sethe V max is considerably less than that observed for quence encoding UGT1A7l is part of a larger cluster of rabbit UGT1A4. Overall, the characterization of rabbit highly related genes. The UGT1A7l RNA is expressed UGT1A7l suggests that this protein represents the orin both neonatal and adult liver, and unlike rat tholog of the human UGT1A7, which to date has not UGT1A2 which is inducible with Ah receptor ligands been identified. ᭧ 1997 Academic Press such as polycyclic aromatic hydrocarbons, rabbit UGT1A7l is not regulated when animals are exposed to these inducers. Following expression of UGT1A7l in COS-1 cells, glucuronidation activity was identified for The UDP-glucuronosyltransferases (UGTs) 3 are a small phenolic molecules like 4-nitrophenol, bulky superfamily of catalytic enzymes involved in the detoxification of endogenous and exogenous compounds. 1 Nomenclature used in this article is based upon recommenda-By converting compounds to water-soluble molecules tions made at the VIIIth International Meeting on Glucuronidation, through the catabolic addition of glucuronic acid, the held May 1996 at the University of Iowa. The human UGT1 locus is UGTs serve to process these substrates for elimination encoded by 12 exon 1 cassettes (Presented by Dr. Owens, NIH), each of which encodes the first 282 amino acids of the UGT1A proteins. in either the bile or urine. The list of potential sub-The proteins encoded by these exons have been characterized as strates is diverse and includes endogenous compounds UGT1A1 through UGT1A12, respectively. In rodents, a similar panel such as hormones and steroids, bilirubin, bile acids of exon 1 sequences (27) flank conserved exons 2-5. These have been and retinoic acids, as well as exogenous agents such 357