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.

ABSTRACT:Treatment of rats with the microsomal enzyme inducers pregnenolone-16␣-carbonitrile (PCN), 3-methylcholanthrene (3-MC), and Aroclor 1254 [PCB (polychlorinated biphenyl)] has been shown to decrease circulating levels of thyroid hormones as well as increase microsomal glucuronidation of thyroxine (T 4 ). In addition, PCN increases triiodothyronine (T 3 ) uridine diphosphate glucuronosyltransferase (UGT) activity. Members of the UGT1A family are believed to glucuronidate T 4 , specifically UGT1A1 and UGT1A6, whereas the UGT2 family is believed to glucuronidate T 3 , namely UGT2B2. The purpose of this study was to determine whether the aforementioned microsomal enzyme inducers increase the mRNAs that encode these and other UGT enzymes in rat liver. Male Sprague-Dawley rats were fed a control diet or a diet containing PCN (1000 ppm), 3-MC (250 ppm), or PCB (100 ppm) for 7 days, at which time livers were collected. Increases in mRNA were detected by QuantiGene branched DNA signal amplification. A 3-fold increase in UGT1A1 mRNA was produced by PCN in addition to increases in UGT1A2 (4-fold) and UGT1A5 (2-fold) mRNA. PCN affected neither UGT2B2 nor any other UGT2B mRNA level. 3-MC and PCB increased UGT1A6 mRNA 6-and 4-fold, respectively. 3-MC and PCB each increased UGT1A7 mRNA 4-fold but did not significantly increase any other UGT mRNAs. These findings suggest that PCN enhances T 4 UGT activity by increased expression of UGT1A1 and that 3-MC and PCB enhance T 4 UGT activity by increased expression of UGT1A6. These findings also suggest that increased T 3 UGT activity produced by PCN is due to a mechanism other than increased transcription of UGT2B2, possibly increased UGT2B2 protein or induction of another UGT enzyme.

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Nafadotride has been proposed as a selective antagonist for the D3 dopamine receptor. This drug has been shown to exhibit selectivity between D2 and D3 dopamine receptors in in vitro assay systems; however, the in vivo D2/D3 selectivity of the compound has not been determined. In this study, protection against inactivation by EEDQ was used as a measure of in vivo occupancy of D2 receptors by behaviorally relevant doses of nafadotride (0.1-10 mg/kg, s.c. and i.p.) in adult, male Sprague-Dawley rats. Ex vivo [3H]spiperone binding was then determined in striatal membranes, l-Nafadotride (10 mg/kg) protected 71% of D2 receptors after s.c. administration; 40% after i.p. administration. Protection of 13% of D2 receptors was observed at a dose of 3 mg/kg (s.c.). These data suggest that blockade of D2 receptors contributes to the pharmacological effects of nafadotride when administered at doses above 1 mg/kg (s.c.) or 3 mg/kg (i.p.).