Distribution and inducibility by 3-methylcholanthrene of family 1 UDP-glucuronosyltransferases in the rat gastrointestinal tract.
UDP-Glucuronosyltransferases (UGT) catalyze the glucuronidation of a broad spectrum of endobiotic and xenobiotic substrates. The resulting glucuronides are more hydrophilic, facilitating renal and biliary excretion. Apart from hepatic glucuronidation, high rates of gastrointestinal glucuronidation have been observed. The aim of this study was to characterize the expression of family 1 UGTs (UGT1A) in liver, kidney, and all parts of the rat gastrointestinal tract by reverse transcription polymerase reaction (RT-PCR), Northern blot, and xenobiotic induction experiments. RT-PCR experiments were performed with primers specific for all known rat UGT1A mRNAs. UGT1A1, UGT1A6, and UGT1A7 were expressed in liver, kidney, and the gastrointestinal tract. UGT1A5 transcripts were detected in liver, but not in kidney or gastrointestinal tissue. In contrast, UGT1A2 and UGT1A3 were not expressed in liver or kidney, but were detected in intestine. Low levels of UGT1A3 were detectable in duodenum and jejunum. UGT1A2 was abundantly expressed in the small intestine; expression levels in the stomach and the large intestine were low. Quantitative evaluation of RNA levels by Northern blot revealed expression in gradients, with highest UGT1A mRNA levels in duodenum and decreasing levels in the small and large intestine. Only UGT1A6 was expressed at high levels in the rectum. Rats treated with 3-methylcholanthrene (3-MC) displayed a 10-fold induction of hepatic UGT1A6 and UGT1A7 mRNAs. In gastric tissues and in intestine, induction was 4-fold and 2-fold, respectively. In contrast to the constitutive expression of UGT1A7 in kidney, UGT1A6 was inducible in the liver. Effects of 3-MC on UGT1A1 expression revealed downregulation in the liver and highly variable effects in duodenum and stomach. This study demonstrates tissue-specific expression and tissue-specific induction patterns in rat liver, kidney, and gastrointestinal tract, which may represent the physiological basis of tissue-specific glucuronidation in rats.
Grams
B
B
Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany.
Harms
A
A
Braun
S
S
Strassburg
C P
CP
Manns
M P
MP
Obermayer-Straub
P
P
D000818:Animals; D015152:Blotting, Northern; D003001:Cloning, Molecular; D004064:Digestive System / Q000201:enzymology*; D004386:Duodenum / Q000201:enzymology; D004790:Enzyme Induction; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis* / Q000737:chemistry*; D007583:Jejunum / Q000201:enzymology; D007668:Kidney / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D008748:Methylcholanthrene / Q000378:metabolism*; D008954:Models, Biological; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution
D012333:RNA, Messenger; D008748:Methylcholanthrene; D014453:Glucuronosyltransferase