Functional heterogeneity of UDP-glucuronosyltransferase activities in C57BL/6 and DBA/2 mice

Bock, Karl Walter; Lilienblum, Werner; Pfeil, H.

doi:10.1016/0006-2952(82)90015-6

Cited by 33 publications

(4 citation statements)

References 27 publications

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“…Therefore, it seems that a strain difference in the control of UGT induction following PCN treatment may exist in mice. This conclusion is analogous to the difference in induction of phenol UGT activities observed in C57BL/6 and DBA/2 mice, which are responsive and nonresponsive to 3-MCtype inducers, respectively (Bock et al, 1982). Further studies are necessary to elucidate possible mechanisms underlying this strain difference in UGT induction by PCN.…”

Section: Chen Et Alsupporting

confidence: 66%

NUCLEAR RECEPTOR, PREGNANE X RECEPTOR, IS REQUIRED FOR INDUCTION OF UDP-GLUCURONOSYLTRANSFERASES IN MOUSE LIVER BY PREGNENOLONE-16α-CARBONITRILE

Chen

Staudinger²,

Klaassen³

2003

Drug Metab Dispos

109

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The aim of this study was to determine the role of pregnane X receptor (PXR) in the induction of UDP-glucuronosyltransferases (UGTs) by pregnenolone-16␣-carbonitrile (PCN). Four-to sixmonth-old male wild-type and PXR-null mice received control or PCN-treated (1500 ppm) diet for 21 days. On day 22, livers were taken to prepare microsomes and total RNA to determine UGT activity and mRNA levels, respectively. In wild-type mice, PCN treatment significantly increased UGT activities toward bilirubin, 1-naphthol, chloramphenicol, thyroxine, and triiodothyronine. On control diet, the UGT activities toward the above substrates (except for 1-naphthol) in the PXR-null mice were significantly higher than those of wild-type mice. However, UGT activities in PXR-null mice were not increased by PCN. In agreement with the above findings, mRNA levels of mouse Ugt1a1 and Ugt1a9, which are involved in the glucuronidation of bilirubin and phenolic compounds, were increased about 100% in wild-type mice following PCN treatment, whereas the expression of Ugt1a2, 1a6, and 2b5 was not affected. In contrast, PCN treatment had no effect on the mRNA levels of these UGTs in PXR-null mice. Taken together, these results indicate that PCN treatment induces glucuronidation in mouse liver, and that PXR regulates constitutive and PCNinducible expression of some UGTs.

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Section: Chen Et Alsupporting

confidence: 66%

NUCLEAR RECEPTOR, PREGNANE X RECEPTOR, IS REQUIRED FOR INDUCTION OF UDP-GLUCURONOSYLTRANSFERASES IN MOUSE LIVER BY PREGNENOLONE-16α-CARBONITRILE

Chen

Staudinger²,

Klaassen³

2003

Drug Metab Dispos

109

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“…The V max of M3G formation was found to be significantly higher in SC and SCKO microsomes as compared with controls. The V max value in controls (18.90 Ϯ 0.6 nmol/min ⅐ mg) was close to other published values in the C57BL mouse liver microsomes (Bock et al, 1982;Hanioka et al, 1990). There was no significant difference in BG formation among the three groups, as seen in Fig.…”

Section: Nagar Et Alsupporting

confidence: 87%

Metabolism of Opioids Is Altered in Liver Microsomes of Sickle Cell Transgenic Mice

2004

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Pain in sickle cell anemia (SCA) is clinically managed with opioid analgesics. There are reports that SCA patients tolerate high doses of these drugs without adequate pain relief. The current study investigated the in vitro hepatic metabolism of opioids in mouse models of sickle cell anemia, with the hypothesis that higher dose requirements in SCA could be explained by an increased metabolism rate of opioids. Various rodent cytochrome P450 substrates, i.e., buprenorphine and codeine, and rodent uridine glucuronosyltransferase substrates, i.e., morphine, buprenorphine, and estradiol, were studied. The three groups used were: 1) control C57BL mice, 2) mice with the human ␣-globin and sickle ␤-globin transgenes (SC), and 3) mice with the human ␣-globin and sickle ␤-glo-

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“…This could suggest that E-10-OH-NT is glucuronidated by GT 2 in the rat, but regulatory properties of an enzyme form such as inducibility are expected to be species-different . As such, the potency of phenobarbital-type inducers appears to be stronger in man (Bock et al 1978) and also in mice (Bock et al 1982) towards GT activities of group 1. Therefore, the properties of one G T cannot be extrapolated from one species to another.…”

Section: Discussionmentioning

confidence: 99%

Glucuronidation of the Enantiomers of E‐10‐Hydroxynortriptyline in Human and Rat Liver Microsomes

Dumont

Perry

1987

Pharmacology & Toxicology

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Conjugation of racemic E-10-hydroxynortriptyline (E-10-OH-NT) with glucuronic acid was studied in the liver microsomal fraction of rats and humans. The diastereomeric glucuronides of E-10-OH-NT were resolved and quantitated by HPLC. Only the (+)-enantiomer was glucuronidated in liver microsomes from humans. Rat liver microsomes catalyzed the formation of both glucuronides. Phenobarbital pretreatment of rats increased the glucuronidation of both enantiomers about five-fold. The formation rate of (+)-E-10-OH-NT glucuronide varied from 5.5 to 33.2 pmol/mg x min, in microsomes from 13 humans. High activity was found in individuals previously treated with pentobarbital. Inhibition experiments with human liver microsomes showed that amitriptyline is a potent competitive inhibitor of (+)-E-10-OH-NT glucuronidation. p-Nitrophenol, paracetamol and 2-hydroxydesipramine also inhibited this reaction.

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Functional heterogeneity of UDP-glucuronosyltransferase activities in C57BL/6 and DBA/2 mice

Cited by 33 publications

References 27 publications

NUCLEAR RECEPTOR, PREGNANE X RECEPTOR, IS REQUIRED FOR INDUCTION OF UDP-GLUCURONOSYLTRANSFERASES IN MOUSE LIVER BY PREGNENOLONE-16α-CARBONITRILE

NUCLEAR RECEPTOR, PREGNANE X RECEPTOR, IS REQUIRED FOR INDUCTION OF UDP-GLUCURONOSYLTRANSFERASES IN MOUSE LIVER BY PREGNENOLONE-16α-CARBONITRILE

Metabolism of Opioids Is Altered in Liver Microsomes of Sickle Cell Transgenic Mice

Glucuronidation of the Enantiomers of E‐10‐Hydroxynortriptyline in Human and Rat Liver Microsomes

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