Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, British Columbia, V6T 1Z3, Canada.
Drug Metab Dispos. 2012 Jan;40(1):178-86. doi: 10.1124/dmd.111.042879. Epub 2011 Oct 21.
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 6β-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 16α-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.
银杏内酯是一种天然存在的倍半萜三内酯，具有治疗缺血和神经退行性疾病（如阿尔茨海默病）的潜力。在本研究中，我们研究了银杏内酯对大鼠组成型芳香烃受体（rCAR）和大鼠孕烷 X 受体（rPXR）活性的影响，并与人类 CAR（hCAR）和人类 PXR（hPXR）进行了比较。银杏内酯在荧光素酶报告基因测定中激活 rCAR，并通过 CYP2B1mRNA 和 CYP2B 酶活性（苯甲氧基resorufin O-脱烷基化）测定在培养的大鼠肝细胞中增加 rCAR 靶基因表达。银杏内酯对肝细胞 CYP2B1 表达的这种增加并不伴随着 rCARmRNA 水平的相应增加。与 rCAR 的激活相反，该化学物质在基于细胞的报告基因测定中不影响 rPXR、hCAR 和 hPXR 的活性。与这些结果一致，银杏内酯并未改变大鼠或人肝细胞中 rPXR、hCAR 或 hPXR 靶基因的表达，如 CYP3A23、CYP2B6、CYP3A4mRNA 测定和 CYP3A（睾酮 6β-羟化）和 CYP2B6（丁丙诺啡羟化）酶活性测定所示。银杏内酯不是 rPXR、hCAR 或 hPXR 的拮抗剂，因为它没有减弱孕烯醇酮 16α-氰化物对 rPXR 的激活、6-(4-氯苯基)咪唑[2,1-b][1,3]噻唑-5-甲酰醛 O-(3,4-二氯苄基)肟对 hCAR 的激活或利福平对 hPXR 的激活在报告基因测定中。总之，银杏内酯是 rCAR 的激活剂，而不是 rPXR、hCAR 或 hPXR 的配体。同样，它是大鼠 CYP2B1 的诱导剂，但不是大鼠 CYP3A23、人 CYP2B6 或人 CYP3A4 的诱导剂。
