UDP-Glucuronosyltransferase 1a Enzymes Are Present and Active in the Mouse Blastocyst

Collier, Abby C.; Yamauchi, Yasuhiro; Sato, Brittany L.M.; Rougée, L.; Ward, Monika A.

doi:10.1124/dmd.114.059766

Cited by 6 publications

(5 citation statements)

References 29 publications

(28 reference statements)

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“…When discussing ontogeny, the profound effects of steroidal axes activating in adolescence is sometimes lost in the rush to discern molecular genetic effects. There is evidence that several of the UGT1A and 2B isoforms can be induced by sex steroids and sex steroid precursors such as gonadotropin‐releasing hormone . Certainly, these data support the contention that part of the ontogenetic process for activating UGTs may be the increase in steroids in adolescence, at least as far as UGT coexpression is concerned, as we found clear breakpoints in the data for correlations at or around 12 years of age.…”

Section: Discussionsupporting

confidence: 82%

Coexpression of Human Hepatic Uridine Diphosphate Glucuronosyltransferase Proteins: Implications for Ontogenetic Mechanisms and Isoform Coregulation

Liu

Badée

Takahashi

et al. 2019

The Journal of Clinical Pharma

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Uridine diphosphate glucuronosyltransferases (UGTs) catalyze glucuronidation to facilitate systemic and local clearance of numerous chemicals and drugs. To investigate whether UGT expression is coregulated in human liver, we analyzed the protein expression of UGTs 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, 3A1, and 3A2 using western blots from 164 healthy human liver samples, comparing expression with age and sex. UGT1A6 levels were significantly higher in children than adults, and UGT3A1 and 3A2 expression significantly increased with age from childhood to age >65 yearas. In children aged <18 years, UGT1A4/1A9 protein expression was significantly correlated, but not for adults aged >18 years. UGT1A3 expression was always significantly correlated with other UGT1A isoforms in all adults aged >18 years. In individuals aged ࣙ12 years, expression of UGT1A1/1A4, UGT1A1/1A6, UGT1A1/1A9, and UGT1A4/1A6 significantly correlated, which was not observed in children aged <12 years. In contrast, UGT1A4/2B7 showed significant correlation in children aged <12 years, but not in individuals aged ࣙ12 years, and this was observed in female but not male individuals. Expression of UGT1A6/1A9 and UGT3A1/3A2 correlated in the entire sample population, but UGT3As did not correlate with other UGTs. These correlations were sex dependent, as UGT1A3/1A1, UGT1A4/2B7 and UGT3A1/3A2 correlated more highly in male than female individuals, while UGT1A4/1A6 protein correlated more significantly in female than male individuals. This is the first report on the ontogeny of UGT3A isoforms, showing maximal expression in the elderly, and is the first demonstration that UGT isoforms commonly coexpress in vivo, in both age-dependent and sex-dependent manners.

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Section: Discussionsupporting

confidence: 82%

Coexpression of Human Hepatic Uridine Diphosphate Glucuronosyltransferase Proteins: Implications for Ontogenetic Mechanisms and Isoform Coregulation

Liu

Badée

Takahashi

et al. 2019

The Journal of Clinical Pharma

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“…Buckley et al [55] have shown that Ugt1a, Ugt2a, Ugt2b and Ugt3a are expressed in mouse placenta. Although studies of rodent fetal livers showed glucuronidation activity, expression of specific Ugt isoforms in mouse fetal livers has not yet been fully described [56, 57]. In Abcb1a -/- / 1b -/- and Abcb1a -/- / 1b -/- / Abcg2 -/- mice, maternal plasma AUC of NBUP-G was increased 3-4-fold compared to wild-type mice (Table 2); however, fetal AUC of NBUP-G was increased only 1.7-2.0-fold (Table 5), indicating a low membrane permeability of NBUP-G which makes sense as NBUP-G is much more water soluble than its parent NBUP.…”

Section: Discussionmentioning

confidence: 99%

P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to norbuprenorphine

Liao

Gao

Shireman

et al. 2017

Pharmacological Research

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Norbuprenorphine is the major active metabolite of buprenorphine which is commonly used to treat opiate addiction during pregnancy. Norbuprenorphine produces marked respiratory depression and was 10 times more potent than buprenorphine. Therefore, it is important to understand the mechanism that controls fetal exposure to norbuprenorphine, as exposure to this compound may pose a significant risk to the developing fetus. P-gp/ABCB1 and BCRP/ABCG2 are two major efflux transporters regulating tissue distribution of drugs. Previous studies have shown that norbuprenorphine, but not buprenorphine, is a P-gp substrate. In this study, we systematically examined and compared the roles of P-gp and BCRP in determining maternal brain and fetal distribution of norbuprenorphine using transporter knockout mouse models. We administered 1 mg/kg norbuprenorphine by retro-orbital injection to pregnant FVB wild-type, Abcb1a-/-/1b-/- and Abcb1a-/-/1b-/-/Abcg2-/- mice on gestation day 15. The fetal AUC of norbuprenorphine was ∼64% of the maternal plasma AUC in wild-type mice, suggesting substantial fetal exposure to norbuprenorphine. The maternal plasma AUCs of norbuprenorphine in Abcb1a-/-/1b-/-and Abcb1a-/-/1b-/-/Abcg2-/-mice were ∼2 times greater than that in wild-type mice. Fetal AUCs in Abcb1a-/-/1b-/- and Abcb1a-/-/1b-/-/Abcg2-/- mice were also increased compared to wild-type mice; however, the fetal-to-maternal plasma AUC ratio remained relatively unchanged by the knockout of Abcb1a/1b or Abcb1a/1b/Abcg2. In contrast, the maternal brain-to-maternal plasma AUC ratio in Abcb1a-/-/1b-/- or Abcb1a-/-/1b-/-/Abcg2-/- mice was increased ∼30-fold compared to wild-type mice. Protein quantification by LC-MS/MS proteomics revealed significantly higher amounts of P-gp protein in the wild-type mice brain than that in the placenta. These results indicate that fetal exposure to norbuprenorphine is substantial and that P-gp has a minor impact on fetal exposure to norbuprenorphine, but plays a significant role in restricting its brain distribution. The differential impacts of P-gp on norbuprenorphine distribution into the brain and fetus are likely, at least in part, due to the differences in amounts of P-gp protein expressed in the blood-brain and blood- placental barriers. BCRP is not as important as P-gp in determining both the systemic and tissue exposure to norbuprenorphine. Finally, fetal AUCs of the metabolite norbuprenorphine-β-D-glucuronide were 3-7 times greater than maternal plasma AUCs, while the maternal brain AUCs were <50% of maternal plasma AUCs, suggesting that a reversible pool of conjugated metabolite in the fetus may contribute to the high fetal exposure to norbuprenorphine.

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“…As previously reported, UDP-UGT is another enzyme associated with detoxification (130), which was found to be increased by parathion (UGT1A1 and UGT2B genes) and decreased by estrogen; however, there was no difference in these genes when the substances were used together (34). Clinical studies have shown an increase in the UGT1A1 and UGT2B gene expression in ovarian cancer (119); therefore, it can be a reliable molecular biomarker for the risk of cancer.…”

Section: Parathion and Malathion Induce Metabolic Alterationsmentioning

confidence: 67%

Signs of carcinogenicity induced by parathion, malathion, and estrogen in human breast epithelial cells (Review)

2021

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Cancer development is a multistep process that may be induced by a variety of compounds. Environmental substances, such as pesticides, have been associated with different human diseases. Organophosphorus pesticides (OPs) are among the most commonly used insecticides. Despite the fact that organophosphorus has been associated with an increased risk of cancer, particularly hormone-mediated cancer, few prospective studies have examined the use of individual insecticides. Reported results have demonstrated that OPs and estrogen induce a cascade of events indicative of the transformation of human breast epithelial cells. In vitro studies analyzing an immortalized non-tumorigenic human breast epithelial cell line may provide us with an approach to analyzing cell transformation under the effects of OPs in the presence of estrogen. The results suggested hormone-mediated effects of these insecticides on the risk of cancer among women. It can be concluded that, through experimental models, the initiation of cancer can be studied by analyzing the steps that transform normal breast cells to malignant ones through certain substances, such as pesticides and estrogen. Such substances cause genomic instability, and therefore tumor formation in the animal, and signs of carcinogenesis in vitro. Cancer initiation has been associated with an increase in genomic instability, indicated by the inactivation of tumor-suppressor genes and activation of oncogenes in the presence of malathion, parathion, and estrogen. In the present study, a comprehensive summary of the impact of OPs in human and rat breast cancer, specifically their effects on the cell cycle, signaling pathways linked to epidermal growth factor, drug metabolism, and genomic instability in an MCF-10F estrogen receptor-negative breast cell line is provided.

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UDP-Glucuronosyltransferase 1a Enzymes Are Present and Active in the Mouse Blastocyst

Cited by 6 publications

References 29 publications

Coexpression of Human Hepatic Uridine Diphosphate Glucuronosyltransferase Proteins: Implications for Ontogenetic Mechanisms and Isoform Coregulation

Coexpression of Human Hepatic Uridine Diphosphate Glucuronosyltransferase Proteins: Implications for Ontogenetic Mechanisms and Isoform Coregulation

P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to norbuprenorphine

Signs of carcinogenicity induced by parathion, malathion, and estrogen in human breast epithelial cells (Review)

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