title: Tissue-specific regulation of canine intestinal and hepatic phenol and morphine UDP-glucuronosyltransferases by beta-naphthoflavone in comparison with humans.
abstract: UDP-glucuronosyltransferases (UGTs) are regulated in a species- and tissue-dependent manner by endogenous and environmental factors. The present study was undertaken to further our knowledge about regulation of UGTs in dogs, a species widely used in preclinical safety evaluation. beta-Naphthoflavone (BNF) was selected as a known aryl hydrocarbon receptor agonist and antioxidant-type inducer. The latter group of inducers is intensively investigated as dietary chemoprotectants against colon cancer. Dog UGTs were investigated in comparison with related human UGTs by examples, (i) expression of dog UGT1A6, the first sequenced dog phenol UGT, and (ii) morphine UGT activities, responsible for intestinal and hepatic first-pass metabolism of morphine. The following results were obtained: (i) dog UGT1A6 was found to be constitutively expressed in liver and marginally increased by BNF treatment. Expression was low in small intestine but ca. 6-fold higher in colon than for example in jejunum. Conjugation of 4-methylumbelliferone, one of the substrates of dog UGT1A6, was also enhanced 7-fold in colonic compared to jejunal microsomes. (ii) Compared to the corresponding human tissues, canine 3-O- and 6-O-morphine UGT activities were found to be >10-fold higher in dog liver and ca. 10-fold lower in small intestinal microsomes. Small intestinal morphine and 4-hydroxybiphenyl UGT activities appeared to be moderately (2- to 3-fold) induced by oral treatment with BNF. (iii) In contrast to dogs, morphine UGT activities were found to be similar in homogenates from human enterocytes and liver. The results suggest marked differences in tissue-specific regulation of canine vs. human hepatic and intestinal phenol or morphine UGTs.
authors: Institute of Toxicology, University of Tübingen, Tübingen, Germany. bock@uni-tuebingen.de
authors: Karl Walter
authors: KW
authors: Bock
authors: Barbara S
authors: BS
authors: Bock-Hennig
authors: Peter A
authors: PA
authors: Münzel
authors: Jens O
authors: JO
authors: Brandenburg
authors: Christoph T
authors: CT
authors: Köhle
authors: Matthew G
authors: MG
authors: Soars
authors: Rob J
authors: RJ
authors: Riley
authors: Brian
authors: B
authors: Burchell
authors: Oliver
authors: O
authors: von Richter
authors: Michel F
authors: MF
authors: Eichelbaum
authors: Stellan
authors: S
authors: Swedmark
authors: Achim
authors: A
authors: Orzechowski
mesh_terms: D000818:Animals; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D009020:Morphine / Q000378:metabolism*; D009928:Organ Specificity; D019800:Phenol / Q000378:metabolism*; D013045:Species Specificity; D019324:beta-Naphthoflavone / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D019800:Phenol; D019324:beta-Naphthoflavone; D009020:Morphine; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase