Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain.
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Sakakibara Y, Katoh M, Kondo Y, Nadai M
Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain.
Drug Metab Dispos. 2016 Mar;44(3):370-7. doi: 10.1124/dmd.115.067439. Epub 2015 Dec 18.
- PubMed ID
- 26684499 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Phenobarbital UDP-glucuronosyltransferase 2B7 Protein Humans UnknownInducerDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareCanagliflozinPrimidone The serum concentration of Canagliflozin can be decreased when it is combined with Primidone. CanagliflozinMethylphenobarbital The serum concentration of Canagliflozin can be decreased when it is combined with Methylphenobarbital. CanagliflozinPhenobarbital The serum concentration of Canagliflozin can be decreased when it is combined with Phenobarbital.