Tissue mRNA Expression of the Rat UDP-Glucuronosyltransferase Gene Family

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:UDP-Glucuronosyltransferases (UGTs) are phase II biotransformation enzymes that glucuronidate numerous endobiotic and xenobiotic substrates. Glucuronidation increases the water solubility of the substrate and facilitates renal and biliary excretion of the resulting glucuronide conjugate. UGTs have been divided into two gene families, UGT1 and UGT2. Tissue distribution of UGTs has not been thoroughly examined, and such data could provide insight into the importance of individual UGT isoforms in specific tissues and to the pharmacokinetics and target organ toxicity of UGT substrates. Therefore, the aim of this study was to determine mRNA levels of rat UGT1 and UGT2 family members in liver, kidney, lung, stomach, duodenum, jejunum, ileum, large intestine, cerebellum, and cerebral cortex, as well as nasal epithelium for UGT2A1. Tissue levels of UGT mRNA were detected using branched DNA signal amplification analysis. Three UGT isoforms, UGT1A1, UGT1A6, and UGT2B12, were detected in many tissues, whereas distribution of other UGT isoforms was more tissue-specific. For example, UGT2A1 was detected predominantly in nasal epithelium. Additionally, UGT1A5, UGT2B1, UGT2B2, UGT2B3, and UGT2B6 were detected primarily in liver. Furthermore, detection of UGT1A2, UGT1A3, UGT1A7, and UGT2B8 was somewhat specific to gastrointestinal (GI) tract. However, not all of these UGTs were detected in all portions of the GI tract. UGT1A8 was unique in that it was barely detectable in any of the tissues examined. In conclusion, some UGT isoforms were expressed in multiple tissues, whereas other UGT isoforms were predominantly expressed in a certain tissue such as nasal epithelium, liver, or GI tract.

Characterization of Bucolome N-Glucuronide Formation: Tissue Specificity and Identification of Rat UDP-Glucuronosyltransferase Isoform (s)

“…They also reported that mRNAs of UGT1A2, UGT1A3, and UGT1A7, which showed BCP-NG-producing activity in our study, were mainly present in the digestive tract, and their expressions were very low in the liver. Furthermore, they confirmed that UGT2B1, UGT2B2, UGT2B3, UGT2B6, and UGT2B12 of the UGT 2B subfamily were expressed mainly in the liver [22], in which the total mRNA expression level of UGT2B1, UGT2B3, and UGT2B6, which showed BCP-NG-producing activity in our study, was lower than that of UGT1A1.…”

“…On the basis of these findings of mRNA expression level [22] and BCP-NG-producing activity, the main UGT isoform responsible for BCP-NG formation in the rat liver may be UGT1A1, and UGT2B1, UGT2B3, and UGT2B6 may be supplementarily involved.…”

“…Shelby et al [22] reported on the UGT isoform distribution at the mRNA level in 10 rat tissues (liver, kidney, lung, stomach, duodenum, jejunum, ileum, large intestine, cerebellum, and cerebral cortex), in which 3 UGT isoforms (UGT1A1, UGT1A6, and UGT2B12) were detected in many tissues, but the distributions of other UGT isoforms were tissue-specific. However, UGT1A6 and UGT2B12 showed no BCP-NG-producing activity.…”

A physiological role for glucuronidated thyroid hormones: Preferential uptake by H9c2(2-1) myotubes

“…The liver is the predominant site of expression of many UGT isoforms (Shelby et al, 2003), but extrahepatic sources of UGT activity have been found in other organs such as the kidney, skin, lung and small intestine (Grams et al, 2000;Turgeon et al, 2001) and, in smaller amounts, spleen, thymus, brain and heart (Burchell and Coughtrie, 1989). We have demonstrated that glucuronidated iodothyronines are synthesized and secreted by cardiac fibroblasts, not cardiomyocytes, obtained from neonatal rat heart (van der Heide et al, 2002).…”

Hepatic and Intestinal Multidrug Resistance-Associated Protein 2: Transcriptional and Post-transcriptional Regulation by Xenobiotics

“…Particularly, the highest concentration of this transporter is found in the liver and intestine [ ], two organs playing a prominent role in xenobiotic detoxiication commonly known as "irst-pass metabolism and clearance". Protein expression of MRP2 is highest in enterocytes of the proximal small intestine, decreasing in direction to the terminal ileum [ ], gradient shared with the expression of phase II metabolizing enzymes such as GST and UGT [9,10], thus suggesting that metabolism and transport processes may act coordinately. In the liver, the major biotransformation organ, MRP2 is abundantly expressed in the bile canalicular membranes of the hepatocyte [11], where it plays a role in bile formation through secretion of endogenous substrates such as glutathione GSH and glutathione conjugates.…”