Endocrine Center, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo 105-8470, Japan.
Toxicol Sci. 2011 Oct;123(2):460-70. doi: 10.1093/toxsci/kfr178. Epub 2011 Jul 8.
Steroid and xenobiotic receptor (SXR) is activated by endogenous and exogenous chemicals including steroids, bile acids, and prescription drugs. SXR is highly expressed in the liver and intestine, where it regulates cytochrome P450 3A4 (CYP3A4), which in turn controls xenobiotic and endogenous steroid hormone metabolism. However, it is unclear whether Food and Drug Administration (FDA)-approved plasticizers exert such activity. In the present study, we evaluated the effects of FDA-approved plasticizers on SXR-mediated transcription in vitro by luciferase reporter, SXR-coactivator interaction, quantitative real-time PCR analysis of CYP3A4 expression, CYP3A4 enzyme activity assays, and SXR knockdown. Rats, treated with gavage and intraperitoneal injection of compounds, were examined for CYP3A1 expression in vivo. We found that four of eight FDA-approved plasticizers increased SXR-mediated transcription. In particular, acetyl tributyl citrate (ATBC), an industrial plasticizer widely used in products such as food wrap, vinyl toys, and pharmaceutical excipients, strongly activated human and rat SXR. ATBC increased CYP3A4 messenger RNA (mRNA) levels and enzyme activity in the human intestinal cells but not in human liver cells. Similarly, CYP3A1 mRNA levels were increased in the intestine but not the liver of ATBC-treated rats. These in vitro and in vivo results suggest that ATBC specifically induces CYP3A in the intestine by activating SXR. We suggest that ATBC-containing products be used cautiously because they may alter metabolism of endogenous steroid hormones and prescription drugs.
甾体和异源生物受体（SXR）被内源性和外源性化学物质激活，包括甾体、胆汁酸和处方药物。SXR 在肝脏和肠道中高度表达，在那里它调节细胞色素 P450 3A4（CYP3A4），进而控制异源生物和内源性甾体激素代谢。然而，尚不清楚食品和药物管理局（FDA）批准的增塑剂是否具有这种活性。在本研究中，我们通过荧光素酶报告基因、SXR 共激活因子相互作用、CYP3A4 表达的定量实时 PCR 分析、CYP3A4 酶活性测定和 SXR 敲低，评估了 FDA 批准的增塑剂对 SXR 介导的转录的体外影响。通过灌胃和腹腔注射化合物处理大鼠，体内检测 CYP3A1 的表达。我们发现，在八种 FDA 批准的增塑剂中，有四种增加了 SXR 介导的转录。特别是，乙酰三丁基柠檬酸酯（ATBC），一种广泛用于食品包装、乙烯基玩具和药物赋形剂等产品的工业增塑剂，强烈激活了人源和大鼠源 SXR。ATBC 增加了人肠细胞中 CYP3A4 信使 RNA（mRNA）水平和酶活性，但不增加人肝细 胞中的 CYP3A4 mRNA 水平。同样，在 ATBC 处理的大鼠中，CYP3A1 mRNA 水平在肠道中增加，但在肝脏中没有增加。这些体外和体内结果表明，ATBC 通过激活 SXR 特异性诱导肠道中的 CYP3A。我们建议谨慎使用含有 ATBC 的产品，因为它们可能会改变内源性甾体激素和处方药物的代谢。
