Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain

Sakakibara, Yukiko; Katoh, Miki; Kondo, Yuya; Nadai, Masayuki

doi:10.1124/dmd.115.067439

Cited by 13 publications

(16 citation statements)

References 47 publications

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“…25) Following PB treatment, Ugt1a6 mRNA was induced 3.0-and 2.9-fold in the striatum and thalamus, respectively. 33) These results are inconsistent with the hypothesis mentioned above that Ugt1a6 and Ugt1a7 are involved in this glucuronidation. In addition, β-estradiol 3-glucuronidation was not correlated with serotonin (r=−0.18) or APAP (r=0.01) glucuronidation among the eight brain regions.…”

Section: )contrasting

confidence: 57%

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Characterization of β-Estradiol 3-Glucuronidation in Rat Brain

Asai

Sakakibara

Onouchi

et al. 2017

Biological & Pharmaceutical Bulletin

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β-Estradiol is conjugated by uridine 5′-diphosphate-glucuronosyltransferase (UGT) 1A to 3-glucuronide in the human liver. UGT1A has been found in the brain; therefore, UGT1A may be involved in β-estradiol 3-glucuronidation in the brain. In the present study, we aimed to characterize the β-estradiol 3-glucuronidation reaction in the rat brain. β-Estradiol 3-glucuronidation was detected in eight rat brain regions (cerebellum, frontal cortex, parietal cortex, piriform cortex, hippocampus, medulla oblongata, striatum, and thalamus). β-Estradiol 3-glucuronidation in the cerebellum was fitted to the Hill equation (S 50 8.0 µM, n 1.1). In inhibition experiments, β-estradiol 3-glucuronidation was inhibited to 73.6% in the cerebellum by 50 µM bilirubin, whereas it was reduced to 20.5% with 5 µM bilirubin in the liver. Unlike in the liver, Ugt1a1 may not be the main isoform catalyzing this glucuronidation in the brain. Serotonin and acetaminophen at 10 mM inhibited glucuronidation to 1.17 and 25.5%, respectively, in the cerebellum. In induction experiments, the administration of β-naphthoflavone, carbamazepine, and phenobarbital did not increase β-estradiol 3-glucuronidation in the brain except for phenobarbital in the striatum. In addition, β-estradiol 3-glucuronidation was not correlated with serotonin or acetaminophen glucuronidation in the brain, suggesting that Ugt1a6 and Ugt1a7 are not major isoforms of β-estradiol 3-glucuronidation in the rat brain. In the present study, although we were unable to identify the isoform responsible for β-estradiol 3-glucuronidation, we confirmed that β-estradiol could be metabolized to glucuronide in the brain under a different metabolic profile from that in the liver.

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Section: )contrasting

confidence: 57%

“…Ugt1a6 and Ugt1a7 mRNAs in the rat brain have been reported to be induced by treatment with BNF 25) and PB 33) at the same dosages as those in the present study. If β-estradiol 3-glucuronidation is catalyzed mainly by Ugt1a6 and Ugt1a7, this glucuronidation will be increased by the Ugt inducers in vivo.…”

Section: )supporting

confidence: 51%

Characterization of β-Estradiol 3-Glucuronidation in Rat Brain

Asai

Sakakibara

Onouchi

et al. 2017

Biological & Pharmaceutical Bulletin

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“… or Sakakibara et al . . PCR amplification conditions were as follows: initial 10 s at 95 °C; 40 cycles of 5 s at 95 °C and 30 s at 60 °C.…”

Section: Methodsmentioning

confidence: 99%

Expression of UGT1A subfamily in rat brain

Sakakibara

Katoh

Imai

et al. 2016

Biopharm & Drug Disp

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UDP-glucuronosyltransferase (UGT) is an enzyme that catalyses a major phase II reaction in drug metabolism. Glucuronidation occurs mainly in the liver, but UGTs are also expressed in extrahepatic tissues, where they play an important role in local metabolism. UGT1A isoforms catalyse the glucuronidation of several drugs, neurotransmitters and neurosteroids that exert pharmacological and physiological effects on the brain. The aim of the current study was to determine UGT1A mRNA expression levels and glucuronidation activities in different regions of the rat brain (namely the cerebellum, frontal cortex, parietal cortex, piriform cortex, hippocampus, medulla oblongata, olfactory bulb, striatum and thalamus). It was found that all UGT1A isoforms were expressed in all the nine regions, but their expression levels differed between the regions. The difference between the regions of the brain where the mRNA levels were highest and those where they were lowest ranged between 2.1- to 7.8-fold. Glucuronidation activities were measured using the UGT substrates such as mycophenolic acid, p-nitrophenol and umbelliferone. Glucuronidation activity was detected in all nine regions of the brain. Activity levels differed between the regions, and were highest in the cerebellum, medulla oblongata and olfactory bulb. Differences in glucuronidation activity between regions with the highest rates and those with the lowest rates ranged from 5.3- to 10.1-fold. These results will contribute to our current understanding of the physiological and pharmacokinetic roles of drug-metabolizing enzymes in the brain. Copyright © 2016 John Wiley & Sons, Ltd.

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“…Therefore, UGT1A may be involved in local drug metabolism in the brain. It was previously reported that Ugt1a in the rat brain was increased by treatment with typical Ugt inducers, such as β‐naphthoflavone (Sakakibara, Katoh, Kondo, & Nadai, ) and phenobarbital (Sakakibara, Katoh, Kondo, & Nadai, ), indicating that changes in UGT1A expression could affect the efficacy of a central‐acting drug by altering its concentration in the brain.…”

Section: Introductionmentioning

confidence: 99%

Effect of status epilepticus on expression of brain UDP‐glucuronosyltransferase 1a in rats

Asai

Tanaka

Nadai

et al. 2017

Biopharm & Drug Disp

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Status epilepticus (SE) involves severe epileptic seizures that cause oxidative stress in the brain. Oxidative stress is known to influence uridine 5'-diposphate-glucuronosyltransferase (UGT) 1A expression. The present study aimed at elucidating the effect of SE on Ugt1a1, Ugt1a6 and Ugt1a7 expression in the rat brain. Kainic acid was used to create an animal model of SE. Sprague-Dawley rats were treated intraperitoneally with 10 mg/kg kainic acid. Ugt1a1 and Ugt1a7 mRNA levels were increased by SE in the cortex and hippocampus (Ugt1a1: 4.0- and 5.3-fold, respectively; Ugt1a7: 2.8- and 2.5-fold, respectively). Moreover, the induction degree of heme oxygenase-1 mRNA, an oxidative stress marker, was high in these regions, suggesting that oxidative stress could be involved in Ugt1a1 and Ugt1a7 induction. Ugt1a6 was elevated by 1.8-fold in the cortex in both SE and non-response (non-epileptic seizure response) rats, implying that Ugt1a6 induction may be independent from SE. An intraperitoneal single administration of 25 mg/kg diazepam (DZP) for the treatment of SE could attenuate heme oxygenase-1 induction in the cortex, whereas Ugt1a1 was decreased in the hippocampus, but not in the cortex, suggesting that there likely exists an alternative mechanism for Ugt1a1 reduction by DZP treatment. Continuous 14-day administration of DZP inhibited Ugt1a1 induction in the cortex, but did not have an effect on Ugt1a7 induction. This study indicated that SE altered the expression of brain Ugt1a1 and Ugt1a7, which could alter glucuronidation in the brain.

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Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain

Cited by 13 publications

References 47 publications

Characterization of β-Estradiol 3-Glucuronidation in Rat Brain

Characterization of β-Estradiol 3-Glucuronidation in Rat Brain

Expression of UGT1A subfamily in rat brain

Effect of status epilepticus on expression of brain UDP‐glucuronosyltransferase 1a in rats

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