Time-Dependent Induction of Hepatic Cytochrome P450 Enzyme Activity and mRNA Expression by Bilobalide in Rats

Taki, Yuko; Yamazaki, Yuko; Shimura, Fumio; Yamada, Shizuo; Umegaki, Keizo

doi:10.1254/jphs.08198sc

Cited by 23 publications

(10 citation statements)

References 12 publications

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“…Previous ex vivo studies indicate that bilobalide increased rat hepatic CYP2B expression (Deng et al, 2008a;Taki et al, 2009). Likewise, in a cell culture study on rat hepatocytes, bilobalide increased the levels of CYP2B1 mRNA and enzyme activity .…”

Section: Introductionmentioning

confidence: 77%

“…However, two other ex vivo rat studies produced internally inconsistent results on the effects of bilobalide on CYP3A mRNA, protein, and enzyme activity levels, when administered as a single dose of 30 mg/kg (Taki et al, 2009) or multiple doses of 1.5 to 30 mg/kg per day for 10 days (Deng et al, 2008a). Taken together, the data from the ex vivo rat studies are inconclusive.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous ex vivo study, bilobalide increased the activity of rat hepatic microsomal CYP3A (Suzuki et al, 2004). However, data on the effect of this chemical on rat CYP3A mRNA, protein, and enzyme activity are internally inconsistent in each of the other two ex vivo studies (Deng et al, 2008a;Taki et al, 2009). In a cell culture study on rat hepatocytes, bilobalide (3-15 M) did not increase CYP3A mRNA or enzyme activity , whereas in another study, the chemical at lesser concentrations of 2 to 50 ng/ml (equivalent to 0.006 -0.153 M) was reported to apparently increase CYP3A protein expression in rat hepatocytes (Deng et al, 2008b).…”

Section: Introductionmentioning

confidence: 97%

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Species-Dependent and Receptor-Selective Action of Bilobalide on the Function of Constitutive Androstane Receptor and Pregnane X Receptor

Lau

Yang²,

Rajaraman³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Bilobalide is a naturally occurring sesquiterpene trilactone with therapeutic potential in the management of ischemia and neurodegenerative diseases such as Alzheimer's disease. In the present study, we investigated the effect of bilobalide on the activity of rat constitutive androstane receptor (rCAR) and rat pregnane X receptor (rPXR) and compared that with human CAR (hCAR) and human PXR (hPXR). Bilobalide activated rCAR in a luciferase reporter gene assay and increased rCAR target gene expression in cultured rat hepatocytes, as determined by the CYP2B1 mRNA and CYP2B enzyme activity (benzyloxyresorufin O-dealkylation) assays. This increase in hepatocyte CYP2B1 expression by bilobalide was not accompanied by a corresponding increase in rCAR mRNA level. In contrast to the activation of rCAR, the activity of rPXR, hCAR, and hPXR was not influenced by this chemical in cell-based reporter gene assays. Consistent with these results, bilobalide did not alter rPXR, hCAR, or hPXR target gene expression in rat or human hepatocytes, as evaluated by the CYP3A23, CYP2B6, CYP3A4 mRNA assays and the CYP3A (testosterone 6␤-hydroxylation) and CYP2B6 (bupropion hydroxylation) enzyme activity assays. Bilobalide was not an antagonist of rPXR, hCAR, or hPXR, as suggested by the finding that it did not attenuate rPXR activation by pregnenolone 16␣-carbonitrile, hCAR activation by 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime, or hPXR activation by rifampicin in reporter gene assays. In conclusion, bilobalide is an activator of rCAR, whereas it is not a ligand of rPXR, hCAR, or hPXR. Likewise, it is an inducer of rat CYP2B1, but not of rat CYP3A23, human CYP2B6, or human CYP3A4.

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Section: Introductionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Species-Dependent and Receptor-Selective Action of Bilobalide on the Function of Constitutive Androstane Receptor and Pregnane X Receptor

Lau

Yang²,

Rajaraman³

et al. 2011

Drug Metab Dispos

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“…The time setting is considered to be proper for investigating if the induction of CYP3A enzyme was caused by anchusan treatment. This condition is supported by the report showing that there is an increase of CYP3A activity at least up to 24 h after single treatment of bilobalide, an ingredient of ginkgo biloba (22). The liver microsomes were prepared by a conventional fractional centrifugation method (23).…”

Section: Drug Administration and Samplingmentioning

confidence: 74%

In Vivo Inhibition of CYP3A-Mediated Midazolam Metabolism by Anchusan in Rats

et al. 2011

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Abstract. Cytochrome P450 (CYP)-mediated drug interactions caused by Kampo medicine have not been investigated sufficiently. The current study was conducted to reveal the effect of anchusan, a commonly used Kampo formula for gastrointestinal disease, on CYP3A-mediated drug metabolism in rats. The pharmacokinetics of midazolam (MDZ) was investigated after the single or one-week administration of anchusan (500 mg/kg) to evaluate its inhibitory and inducible effect on CYP3A, respectively. MDZ was administrated 16 h after the last anchsan treatment in the multiple dose study, while their intervals were 2 or 16 h in the single dose study. Unexpectedly, the multiple-pretreatment of anchusan increased the AUC of MDZ by 2.4-fold rather than decreasing it, and the CYP3A contents and activities were unchanged in hepatic and intestinal microsomes of these rats. In contrast, no significant inhibitory effects on MDZ metabolism were observed by the single anchusan pretreatment. In vitro study showed that the preincubation of anchusan and some of its component extracts with rat liver microsomes reduced CYP3A activity in a time-and NADPH-dependent manner. These results suggested that anchusan increased the serum MDZ concentration in rats, at least in part, by the time-dependent inhibition of CYP3A.

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“…Concomitant administration of G. biloba also enhanced the hepatotoxicity of acetaminophen via CYP3A induction [147]. However, several of these in vivo studies contradicted cell-based reporter assay findings when bilobalide was implicated as an XME activator [148][149][150]. Evidence from in vitro and animal investigations clearly points to G. biloba extracts and their constituents as inducers of XME and transporter activity.…”

Section: Ginkgo Biloba !mentioning

confidence: 99%

Pharmacokinetic Herb-Drug Interactions (Part 2): Drug Interactions Involving Popular Botanical Dietary Supplements and Their Clinical Relevance

2012

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Introduction !In Part 1 of this review, a discussion of the origins and mechanisms underlying herb-drug interactions was presented. In Part 2, a critical assessment of the available clinical evidence regarding herbdrug interaction potentials for several popular botanical supplements sold in the United States is provided. While the number of botanicals selected for review is not extensive, the approach taken to discern whether a botanical extract poses a risk for producing clinically significant herb-drug in-

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Time-Dependent Induction of Hepatic Cytochrome P450 Enzyme Activity and mRNA Expression by Bilobalide in Rats

Cited by 23 publications

References 12 publications

Species-Dependent and Receptor-Selective Action of Bilobalide on the Function of Constitutive Androstane Receptor and Pregnane X Receptor

Species-Dependent and Receptor-Selective Action of Bilobalide on the Function of Constitutive Androstane Receptor and Pregnane X Receptor

In Vivo Inhibition of CYP3A-Mediated Midazolam Metabolism by Anchusan in Rats

Pharmacokinetic Herb-Drug Interactions (Part 2): Drug Interactions Involving Popular Botanical Dietary Supplements and Their Clinical Relevance

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