Jeong H, Choi S, Song J W, Chen H, Fischer J H
Department of Pharmacy Practice, College of Pharmacy, Universit of Illinois at Chicago, Chicago, IL 60612, USA.
Xenobiotica. 2008 Jan;38(1):62-75. doi: 10.1080/00498250701744633.
The authors recently reported the increased oral clearance of labetalol in pregnant women. To elucidate the mechanism of the elevated oral clearance, it was hypothesized that female hormones, at the high concentrations attainable during pregnancy, enhance hepatic metabolism of labetalol. Labetalol glucuronidation, which is the major elimination pathway of labetalol, was characterized by screening six recombinant human UGTs (UGT1A1, 1A4, 1A6, 1A9, 2B4, and 2B7) for their capacity to catalyse labetalol glucuronidation. The effect of female hormones (progesterone, oestradiol, oestriol, or oestrone) on the promoter activities of relevant UDP glucuronosyltransferases (UGT) was investigated using a luciferase reporter assay in HepG2 cells. The involvement of oestrogen receptor alpha (ERalpha) and pregnane X receptor (PXR) was examined by co-transfecting ERalpha- or PXR-constructs. UGT1A1 and UGT2B7 were identified as the major UGT enzymes producing labetalol glucuronides (trace amount of glucuronide conjugate was formed by UGT1A9). The activities of the UGT1A1 promoter containing PXR response elements were enhanced by progesterone, but not by oestrogens, indicating PXR-mediated induction of UGT1A1 promoter activity by progesterone. Results from semi-quantitative real-time polymerase chain reaction (PCR) assays are consistent with the above findings. This effect of progesterone on UGT1A1 promoter activities was concentration dependent. Promoter activities of UGT2B7 were not affected by either oestrogens or progesterone. The results suggest a potential role for progesterone in regulating labetalol elimination by modulating the expression of UGT1A1, leading to enhanced drug metabolism during pregnancy.
作者最近报道了孕妇拉贝洛尔口服清除率增加。为阐明口服清除率升高的机制，研究人员推测，孕期可达到的高浓度女性激素会增强拉贝洛尔的肝脏代谢。拉贝洛尔葡萄糖醛酸化是拉贝洛尔的主要消除途径，通过筛选六种重组人UGT（UGT1A1、1A4、1A6、1A9、2B4和2B7）催化拉贝洛尔葡萄糖醛酸化的能力来对其进行表征。使用HepG2细胞中的荧光素酶报告基因测定法研究了女性激素（孕酮、雌二醇、雌三醇或雌酮）对相关UDP葡萄糖醛酸基转移酶（UGT）启动子活性的影响。通过共转染ERalpha或PXR构建体来检测雌激素受体α（ERalpha）和孕烷X受体（PXR）的参与情况。UGT1A和UGT2B7被确定为产生拉贝洛尔葡萄糖醛酸化物的主要UGT酶（UGT1A9形成微量葡萄糖醛酸共轭物）。含有PXR反应元件的UGT1A1启动子活性被孕酮增强，但未被雌激素增强，表明孕酮通过PXR介导诱导UGT1A1启动子活性。半定量实时聚合酶链反应（PCR）测定结果与上述发现一致。孕酮对UGT1A1启动子活性的这种影响是浓度依赖性的。UGT2B7的启动子活性不受雌激素或孕酮的影响。结果表明，孕酮在通过调节UGT1A1的表达来调节拉贝洛尔消除方面具有潜在作用，从而导致孕期药物代谢增强。
