title: Quantitative ADME proteomics - CYP and UGT enzymes in the Beagle dog liver and intestine.
abstract: OBJECTIVE
  Beagle dogs are used to study oral pharmacokinetics and guide development of drug formulations for human use. Since mechanistic insight into species differences is needed to translate findings in this species to human, abundances of cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) drug metabolizing enzymes have been quantified in dog liver and intestine.
  
  
  METHODS
  Abundances of enzymes were measured in Beagle dog intestine and liver using selected reaction monitoring mass spectrometry.
  
  
  RESULTS
  Seven and two CYPs were present in the liver and intestine, respectively. CYP3A12 was the most abundant CYP in both tissues. Seven UGT enzymes were quantified in the liver and seven in the intestine although UGT1A11 and UGT1A9 were present only in the intestine and UGT1A7 and UGT2B31 were found only in the liver. UGT1A11 and UGT1A2 were the most abundant UGTs in the intestine and UGT2B31 was the most abundant UGT in the liver. Summed abundance of UGT enzymes was similar to the sum of CYP enzymes in the liver whereas intestinal UGTs were up to four times more abundant than CYPs. The estimated coefficients of variation of abundance estimates in the livers of 14 donors were separated into biological and technical components which ranged from 14 to 49% and 20 to 39%, respectively.
  
  
  CONCLUSIONS
  Abundances of canine CYP enzymes in liver and intestine have been confirmed in a larger number of dogs and UGT abundances have been quantified for the first time. The biological variability in hepatic CYPs and UGTs has also been estimated.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Aki T
authors.initials: AT
authors.lastname: Heikkinen
authors.forename: Arno
authors.initials: A
authors.lastname: Friedlein
authors.forename: Mariette
authors.initials: M
authors.lastname: Matondo
authors.forename: Oliver J D
authors.initials: OJ
authors.lastname: Hatley
authors.forename: Aleksanteri
authors.initials: A
authors.lastname: Petsalo
authors.forename: Risto
authors.initials: R
authors.lastname: Juvonen
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Galetin
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
authors.forename: Ruedi
authors.initials: R
authors.lastname: Aebersold
authors.forename: Jens
authors.initials: J
authors.lastname: Lamerz
authors.forename: Tom
authors.initials: T
authors.lastname: Dunkley
authors.forename: Paul
authors.initials: P
authors.lastname: Cutler
authors.forename: Neil
authors.initials: N
authors.lastname: Parrott
mesh_terms: D000818:Animals; D003106:Colon / Q000201:enzymology*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000378:metabolism*; D004285:Dogs; D005260:Female; D014453:Glucuronosyltransferase / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D007421:Intestine, Small / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D013058:Mass Spectrometry; D008861:Microsomes / Q000201:enzymology; D008954:Models, Biological; D040901:Proteomics / Q000379:methods*; D013045:Species Specificity
chemical_list: D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase