title: Ontogenesis of UDP-glucuronosyltransferase enzymes in sheep.
abstract: UDP glucuronosyltransferases (UGTs) are important for the metabolism of many drugs. To understand the ontogeny of these enzymes in sheep (Ovis aries), knowledge of their expression levels at different developmental stages is important. cDNA sequences of six UGTs (UGT1A1, UGT1A3, UGT1A4, UGT1A6 and UGT1A9) were cloned in sheep liver by rapid amplification of cDNA ends. The mRNA and protein levels of the enzymes in sheep liver (adult n=4; newborn n=3; fetus n=3) were determined using PCR and Western blots. mRNA levels in adult were very high followed by newborn and then fetus. However, no protein bands were detected on the Western blots of sheep hepatic microsomal proteins using several different antibodies against human UGTs. The effect of antenatal glucocorticoid administration was also studied by infusion of cortisol (0.45mg/h; 80h) to another group of fetuses (n=5). This did not result in any significant changes in fetal mRNA levels. However, the correlation observed between the UGT enzymes and hepatocyte nuclear factor 4α (HNF4α) suggests a possible regulatory role for this transcription factor in sheep. We postulate that fetal and newborn lambs may have a reduced ability to metabolize drugs that are substrates of these enzymes.
authors.affiliation: Department of Obstetrics and Gynecology, Child and Family Research Institute, Faculty of Medicine, University of British Columbia, Canada V5Z4H4.
authors.forename: Manoja
authors.initials: M
authors.lastname: Pretheeban
authors.forename: Geoff
authors.initials: G
authors.lastname: Hammond
authors.forename: Stelvio
authors.initials: S
authors.lastname: Bandiera
authors.forename: Wayne
authors.initials: W
authors.lastname: Riggs
authors.forename: Dan
authors.initials: D
authors.lastname: Rurak
mesh_terms: D000818:Animals; D002417:Cattle; D005260:Female; D018507:Gene Expression Regulation, Developmental; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000196:embryology / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012337:RNA, Ribosomal, 18S / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D012756:Sheep / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D051557:Hepatocyte Nuclear Factor 4; D020033:Protein Isoforms; D012333:RNA, Messenger; D012337:RNA, Ribosomal, 18S; D014453:Glucuronosyltransferase