Effect of Adrenalectomy on Expression and Induction of UDP-Glucuronosyltransferase 1A6 and 1A7 in Rats

Sakakibara, Yukiko; Katoh, Miki; Suzuki, Mitsuaki; Kawabe, Ryoko; Iwase, Keisuke; Nadai, Masayuki

doi:10.1248/bpb.b13-00899

Cited by 5 publications

(4 citation statements)

References 29 publications

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“…Ethoxyresorufin O-Deethylase (EROD) Activity EROD activity was determined using the method described by Sakakibara et al 23) In a preliminary study, we confirmed the linearity of the protein concentrations, the substrate concentration, and incubation times. The reaction mixture containing 0.2 mg/mL brain microsomes and 2 µM 7-ethoxyresorufin was incubated at 37°C for 30 min.…”

Section: Methodssupporting

confidence: 70%

Effects of β-Naphthoflavone on Ugt1a6 and Ugt1a7 Expression in Rat Brain

Sakakibara

Katoh

Kondo

et al. 2016

Biological & Pharmaceutical Bulletin

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Uridine 5′-diphosphate-glucuronosyltransferase (UGT) catalyzes a major phase II reaction in a drugmetabolizing enzyme system. Although the UGT1A subfamily is expressed mainly in the liver, it is also expressed in the brain. The purpose of the present study was to elucidate the effect of β-naphthoflavone (BNF), one of the major inducers of drug-metabolizing enzymes, on Ugt1a6 and Ugt1a7 mRNA expression and their glucuronidation in the rat brain. Eight-week-old male Sprague-Dawley rats were treated intraperitoneally with BNF (80 mg/kg), once daily for 7 d. Ugt1a6 and Ugt1a7 mRNA expression increased in the cerebellum and hippocampus (Ugt1a6: 2.1-and 2.3-fold, respectively; Ugt1a7: 1.7-and 2.8-fold, respectively); acetaminophen glucuronidation also increased in the same regions by 4.1-and 2.7-fold, respectively. BNF induced Ugt1a6 and Ugt1a7 mRNA expression and their glucuronidation, and the degree of induction differed among 9 regions. BNF also upregulated CYP1A1, CYP1A2, and CYP1B1 mRNAs in the rat brain. Since the aryl hydrocarbon receptor signaling pathway was activated by BNF, it is indicated that Ugt1a6 and Ugt1a7 were induced via AhR in the rat brain. This study clarified that Ugt1a6 and Ugt1a7 mRNA expression and their enzyme activities were altered by BNF, suggesting that these changes may lead to alteration in the pharmacokinetics of UGT substrate in rat brain.

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Section: Methodssupporting

confidence: 70%

Effects of β-Naphthoflavone on Ugt1a6 and Ugt1a7 Expression in Rat Brain

Sakakibara

Katoh

Kondo

et al. 2016

Biological & Pharmaceutical Bulletin

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“…APAP Glucuronidation. APAP glucuronidation was determined using the method described by Sakakibara et al (2014) with slight modifications. In a preliminary study, we confirmed the linearity of the protein concentrations, substrate concentration, and incubation times.…”

Section: Methodsmentioning

confidence: 99%

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

Sakakibara

Katoh

Kondo

et al. 2015

Drug Metabolism and Disposition

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UDP-glucuronosyltransferase (UGT), a phase II drug-metabolizing enzyme, is expressed in the brain and can catalyze glucuronidation of endogenous and exogenous substrates in the brain. Thus, changes in UGT1A expression could affect homeostasis and drug efficacy. Phenobarbital (PB), a typical inducer of drug-metabolizing enzymes, has been reported to induce oxidative stress and epigenetic changes, which could alter UGT expression in the brain. Here, we aimed to clarify the effects of PB on Ugt1a6 and Ugt1a7 gene expression in rat brains. Sprague-Dawley rats were treated intraperitoneally with PB (80 mg/kg), once daily for 7 days. Ugt1a6 and Ugt1a7 mRNA expression levels were increased in the striatum and thalamus (Ugt1a6, 3.0-and 2.9-fold, respectively; Ugt1a7, 2.6-and 2.6-fold, respectively). Acetaminophen glucuronidation was also increased in the medulla oblongata and thalamus by 1.8-and 1.2-fold, respectively. The induction rates within different brain regions were correlated with Ugt1a6 and Ugt1a7 mRNA expression, and the degree of induction also correlated with that of NF-E2-related factor-2 mRNA. Measurement of oxidative stress markers suggested that PB induced oxidative stress in brain regions in which Ugt1a6 and Ugt1a7 mRNAs were increased. Moreover, histone modifications were altered by PB treatment, resulting in increased histone H3 lysine 4 trimethylation in the striatum and thalamus and decreased histone H3 lysine 9 trimethylation in the thalamus. These results suggested that oxidative stress and histone modifications may promote transcriptional activation of Ugt1a6 and Ugt1a7 genes. In summary, Ugt1a6 and Ugt1a7 mRNA levels were increased by PB treatment, which may alter pharmacokinetics in the brain.

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“…Following surgery, the animals were pair housed with Enviro Dry enrichment/nesting material, provided with powdered as well as pelleted food, and allowed to recover for 4-6 days prior to any drug treatment related to this study. This approach was based on a number of AD studies that used/recommended a 4-6-day recovery period to avoid secondary changes in the body occurring as a result of AD (Miller et al 2016b;Nicolaides et al, 2013;Sakakibara et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

Beta-2 Adrenergic and Glucocorticoid Receptor Agonists Modulate Ozone-Induced Pulmonary Protein Leakage and Inflammation in Healthy and Adrenalectomized Rats

Henriquez

Snow

Schladweiler

et al. 2018

Toxicological Sciences

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We have shown that acute ozone inhalation activates sympathetic-adrenal-medullary and hypothalamus-pituitary-adrenal stress axes, and adrenalectomy (AD) inhibits ozone-induced lung injury and inflammation. Therefore, we hypothesized that stress hormone receptor agonists (β2 adrenergic-β2AR and glucocorticoid-GR) will restore the ozone injury phenotype in AD, while exacerbating effects in sham-surgery (SH) rats. Male Wistar Kyoto rats that underwent SH or AD were treated with vehicles (saline + corn oil) or β2AR agonist clenbuterol (CLEN, 0.2 mg/kg, i.p.) + GR agonist dexamethasone (DEX, 2 mg/kg, s.c.) for 1 day and immediately prior to each day of exposure to filtered air or ozone (0.8 ppm, 4 h/day for 1 or 2 days). Ozone-induced increases in PenH and peak-expiratory flow were exacerbated in CLEN+DEX-treated SH and AD rats. CLEN+DEX affected breath waveform in all rats. Ozone exposure in vehicle-treated SH rats increased bronchoalveolar lavage fluid (BALF) protein, N-acetyl glucosaminidase activity (macrophage activation), neutrophils, and lung cytokine expression while reducing circulating lymphocyte subpopulations. AD reduced these ozone effects in vehicle-treated rats. At the doses used herein, CLEN+DEX treatment reversed the protection offered by AD and exacerbated most ozone-induced lung effects while diminishing circulating lymphocytes. CLEN+DEX in air-exposed SH rats also induced marked protein leakage and reduced circulating lymphocytes but did not increase BALF neutrophils. In conclusion, circulating stress hormones and their receptors mediate ozone-induced vascular leakage and inflammatory cell trafficking to the lung. Those receiving β2AR and GR agonists for chronic pulmonary diseases, or with increased circulating stress hormones due to psychosocial stresses, might have altered sensitivity to air pollution.

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Effect of Adrenalectomy on Expression and Induction of UDP-Glucuronosyltransferase 1A6 and 1A7 in Rats

Cited by 5 publications

References 29 publications

Effects of β-Naphthoflavone on Ugt1a6 and Ugt1a7 Expression in Rat Brain

Effects of β-Naphthoflavone on Ugt1a6 and Ugt1a7 Expression in Rat Brain

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

Beta-2 Adrenergic and Glucocorticoid Receptor Agonists Modulate Ozone-Induced Pulmonary Protein Leakage and Inflammation in Healthy and Adrenalectomized Rats

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