Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27514, USA.
Toxicol Sci. 2010 Feb;113(2):367-79. doi: 10.1093/toxsci/kfp271. Epub 2009 Nov 12.
Triclosan (5-chloro-2-(2,4-dichlorophenoxy)-phenol) is a chlorinated phenolic antibacterial compound found in consumer products. In vitro human pregnane X receptor activation, hepatic phase I enzyme induction, and decreased in vivo total thyroxine (T4) suggest adverse effects on thyroid hormone homeostasis. Current research tested the hypothesis that triclosan decreases circulating T4 via upregulation of hepatic catabolism and transport. Weanling female Long-Evans rats received triclosan (0-1000 mg/kg/day) by gavage for 4 days. Whole blood and liver were collected 24 h later. Total serum T4, triiodothyronine (T3), and thyroid-stimulating hormone (TSH) were measured by radioimmunoassay. Hepatic microsomal assays measured ethoxyresorufin-O-deethylase, pentoxyresorufin-O-deethylase (PROD), and uridine diphosphate glucuronyltransferase enzyme activities. The messenger RNA (mRNA) expression of cytochrome P450s 1a1, 2b1/2, and 3a1/23; UGTs 1a1, 1a6, and 2b5; sulfotransferases 1c1 and 1b1; and hepatic transporters Oatp1a1, Oatp1a4, Mrp2, and Mdr1b was measured by quantitative reverse transcriptase PCR. Total T4 decreased dose responsively, down to 43% of control at 1000 mg/kg/day. Total T3 was decreased to 89 and 75% of control at 300 and 1000 mg/kg/day. TSH did not change. Triclosan dose dependently increased PROD activity up to 900% of control at 1000 mg/kg/day. T4 glucuronidation increased nearly twofold at 1000 mg/kg/day. Cyp2b1/2 and Cyp3a1/23 mRNA expression levels were induced twofold and fourfold at 300 mg/kg/day. Ugt1a1 and Sult1c1 mRNA expression levels increased 2.2-fold and 2.6-fold at 300 mg/kg/day. Transporter mRNA expression levels were unchanged. These data denote important key events in the mode of action for triclosan-induced hypothyroxinemia in rats and suggest that this effect may be partially due to upregulation of hepatic catabolism but not due to mRNA expression changes in the tested hepatic transporters.
三氯生（5-氯-2-（2,4-二氯苯氧基）-苯酚）是一种存在于消费品中的氯化酚类抗菌化合物。体外人体孕烷 X 受体激活、肝Ⅰ相酶诱导和体内总甲状腺素（T4）减少表明对甲状腺激素稳态有不良影响。目前的研究检验了三氯生通过上调肝内分解代谢和转运来降低循环 T4 的假设。我们给新生雌性 Long-Evans 大鼠灌胃三氯生（0-1000mg/kg/天），4 天后收集全血和肝脏。通过放射免疫测定法测量总血清 T4、三碘甲状腺原氨酸（T3）和促甲状腺激素（TSH）。肝微粒体测定法测量了乙氧基 RESO 脱乙基酶、戊氧基 RESO 脱乙基酶（PROD）和尿苷二磷酸葡萄糖醛酸基转移酶的活性。通过定量逆转录 PCR 测量了细胞色素 P450s 1a1、2b1/2 和 3a1/23；UGTs 1a1、1a6 和 2b5；磺基转移酶 1c1 和 1b1；和肝转运蛋白 Oatp1a1、Oatp1a4、Mrp2 和 Mdr1b 的信使 RNA（mRNA）表达。总 T4 呈剂量依赖性降低，在 1000mg/kg/天剂量下降至对照组的 43%。总 T3 在 300 和 1000mg/kg/天剂量下分别降至对照组的 89%和 75%。TSH 没有变化。三氯生剂量依赖性地增加 PROD 活性，在 1000mg/kg/天剂量下增加至对照组的 900%。T4 葡萄糖醛酸化增加近两倍，在 1000mg/kg/天剂量下。Cyp2b1/2 和 Cyp3a1/23mRNA 表达水平增加了两倍和四倍，在 300mg/kg/天剂量下。Ugt1a1 和 Sult1c1mRNA 表达水平增加了 2.2 倍和 2.6 倍，在 300mg/kg/天剂量下。转运蛋白 mRNA 表达水平没有变化。这些数据表示三氯生诱导大鼠甲状腺功能减退症的作用模式中的重要关键事件，并表明这种效应可能部分归因于肝内分解代谢的上调，但不是由于测试的肝转运蛋白的 mRNA 表达变化。
