Neonatal Development of Hepatic UGT1A9: Implications of Pediatric Pharmacokinetics

Miyagi, Shogo John; Milne, A. A.; Coughtrie, Michael W.H.; Collier, Abby C.

doi:10.1124/dmd.111.043752

Cited by 46 publications

(45 citation statements)

References 38 publications

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“…However, if human UGT1 enzymes contribute extensively to BPA metabolism, as we have found to be the case in mice, this concern may not be well-founded. UGT1A9 reaches adult levels by 4 months, and expression of UGT1A1 increases rapidly after birth due to the necessity of bilirubin conjugation, which occurs in the maternal liver via transfer across the placenta prior to birth (Schenker et al, 1964;Onishi et al, 1979;Miyagi et al, 2012). While we cannot rule out the possibility that the predominant role of UGT1s in BPA metabolism is unique to the mouse, the UGT1 family is more closely conserved between species than the UGT2 family, suggesting that members of the UGT1 family may play a major role in BPA glucuronidation in humans.…”

Section: Discussionmentioning

confidence: 99%

Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family

et al. 2015

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UDP-Glucuronosyltransferases (UGTs) conjugate a glucuronyl group from glucuronic acid to a wide range of lipophilic substrates to form a hydrophilic glucuronide conjugate. The glucuronide generally has decreased bioactivity and increased water solubility to facilitate excretion. Glucuronidation represents an important detoxification pathway for both endogenous waste products and xenobiotics, including drugs and harmful industrial chemicals. Two clinically significant families of UGT enzymes are present in mammals: UGT1s and UGT2s. Although the two families are distinct in gene structure, studies using recombinant enzymes have shown considerable overlap in their ability to glucuronidate many substrates, often obscuring the relative importance of the two families in the clearance of particular substrates in vivo. To address this limitation, we have generated a mouse line, termed DUgt2, in which the entire Ugt2 gene family, extending over 609 kilobase pairs, is excised. This mouse line provides a means to determine the contributions of the two UGT families in vivo. We demonstrate the utility of these animals by defining for the first time the in vivo contributions of the UGT1 and UGT2 families to glucuronidation of the environmental estrogenic agent bisphenol A (BPA). The highest activity toward this chemical is reported for human and rodent UGT2 enzymes. Surprisingly, our studies using the DUgt2 mice demonstrate that, while both UGT1 and UGT2 isoforms can conjugate BPA, clearance is largely dependent on UGT1s.

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Section: Discussionmentioning

confidence: 99%

Xenobiotic Metabolism in Mice Lacking the UDP-Glucuronosyltransferase 2 Family

et al. 2015

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“…Of the isoforms studied to date, hepatic UGT1A4, 1A9, 2B7 and 2B15 are absent or have sparingly low activity at birth (Divakaran et al 2014; Miyagi and Collier 2007, 2011; Miyagi et al 2012; Zaya et al 2006), while UGT1A1 activity increases from 0.1 to 1.0 % of adult activities between 30 and 40 weeks of gestation (Kawade and Onishi 1981) and UGT1A6 may be up to 50 % of adult activities at birth (Burchell et al 1989). Hence glucuronidation primarily develops in the postnatal period, independent of gestational age at birth (Burchell et al 1989; Coughtrie et al 1988; Kawade and Onishi 1981; Strassburg et al 2002).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, placental UGTs are likely to have a vital role compensating for a lack of fetal hepatic glucuronidation, since although fetal liver expresses UGT, they are either inactive or have very low activity until after delivery (Burchell et al 1989; Collier et al 2012; Court et al 2011; Kawade and Onishi 1981; Miyagi and Collier 2007, 2011, 2012). This is very interesting because with the exception of cats ( Felis sp. )…”

Section: Introductionmentioning

confidence: 99%

Placental profiling of UGT1A enzyme expression and activity and interactions with preeclampsia at term

Collier

Thévenon

Goh

et al. 2014

Eur J Drug Metab Pharmacokinet

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Placental UDP-glucuronosyltransferase (UGT) enzymes have critical roles in hormone, nutrient, chemical balance and fetal exposure during pregnancy. Placental UGT1A isoforms were profiled and differences between preeclamptic (PE) and non-PE placental UGT expression determined. In third trimester villous placenta, UGT1A1, 1A4, 1A6 and 1A9 were expressed and active in all specimens (n = 10), but UGT1A3, 1A5, 1A7, 1A8 and 1A10 were absent. The UGT1A activities were comparable to human liver microsomes per milligram, but placental microsome yields were only 2 % of liver (1 mg/g of tissue vs. 45 mg/g of tissue). For successful PCR, placental collection and processing within 60 min from delivery, including DNAse and ≥300 ng of RNA in reverse transcription were essential and snap freezing in liquid nitrogen immediately was the best preservation method. Although UGT1A6 mRNA was lower in PE (P < 0.001), there were no other significant effects on UGT mRNA, protein or activities. A more comprehensive tissue sample set is required for confirmation of PE interactions with UGT. Placental UGT1A enzyme expression patterns are similar to the liver and a detoxicative role for placental UGT1A is inferred.

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“…Sulfate conjugation develops fast and glucuronate conjugation develops slowly. The isoform UGT1A9 activity is not present at birth but gradually increases to reach adult levels by 4 months of age [34], whereas UGT1A1 is low at birth and plateaus at 4 months and UGTIA6 is high at birth and increases to adult levels by 14 months [35]. Acetaminophen is frequently used in children and is a substrate of UGT1A6 and to a lesser extent, UGT1A9.…”

Section: Metabolismmentioning

confidence: 99%