Duanmu Z, Dunbar J, Falany C N, Runge-Morris M
Institute of Chemical Toxicology, Wayne State University, Detroit, Michigan 48201, USA.
Toxicol Appl Pharmacol. 2000 May 1;164(3):312-20. doi: 10.1006/taap.2000.8911.
The hypotensive agent minoxidil (6-imino-1, 2-dihydro-1-hydroxy-2-imino-4-piperidinopyrimidine) depends upon aryl sulfotransferase (SULT1)-catalyzed sulfation for its bioactivation. Previous reports suggest that glucocorticoids induce class-specific SULT1 and isoform-specific SULT1A1 gene expression in rat liver. In the present study, rats were treated with the glucocorticoid triamcinolone acetonide (TA, 5 mg/kg/day i.p. x 3 days) or its vehicle, 2% Tween-20, prior to minoxidil, and subsequent effects on mean arterial pressure (MAP), heart rate (HR), and hepatic SULT1 gene expression were characterized. Minoxidil treatment (1.5 mg/kg) resulted in a steady decline in MAP values of 16.3 to 18.6% relative to basal control levels at 35 to 60 min following minoxidil injection. Pentachlorophenol (PCP, 40 micromol/kg i.p.), an inhibitor of SULT1 enzyme activity, effectively ablated the hypotensive effects of minoxidil. By contrast, pretreatment with TA significantly enhanced minoxidil-induced hypotension. Relative to vehicle-treated controls, TA-treated rats displayed a steeper rate of decline in MAP and more profound levels of hypotension with decreases in MAP following minoxidil administration of 27.8%. TA also produced significant increases in hepatic SULT1 mRNA expression (of 271%) and SULT1A1 immunoreactive protein levels (of 273%), relative to vehicle-treated controls. These results provide physiological evidence to support the biological relevance of SULT1A1 induction by glucocorticoids. The data indicate that steroid treatment induces SULT1A1 gene expression and, as a consequence, accentuates the hypotensive effects of minoxidil.
降压药米诺地尔（6-亚氨基-1,2-二氢-1-羟基-2-亚氨基-4-哌啶基嘧啶）的生物活化依赖于芳基磺基转移酶（SULT1）催化的硫酸化作用。先前的报道表明，糖皮质激素可诱导大鼠肝脏中特定类别的SULT1和特定亚型的SULT1A1基因表达。在本研究中，在给予米诺地尔之前，给大鼠腹腔注射糖皮质激素曲安奈德（TA，5 mg/kg/天，共3天）或其溶媒2%吐温-20，然后对平均动脉压（MAP）、心率（HR）和肝脏SULT1基因表达的后续影响进行表征。米诺地尔治疗（1.5 mg/kg）导致注射米诺地尔35至60分钟后，MAP值相对于基础对照水平稳定下降16.3%至18.6%。五氯苯酚（PCP，40 μmol/kg腹腔注射）是SULT1酶活性的抑制剂，可有效消除米诺地尔的降压作用。相比之下，TA预处理显著增强了米诺地尔诱导的低血压。与溶媒处理的对照组相比，TA处理的大鼠MAP下降速率更陡，低血压程度更深，米诺地尔给药后MAP下降27.8%。与溶媒处理的对照组相比，TA还使肝脏SULT1 mRNA表达显著增加（271%），SULT1A1免疫反应蛋白水平显著增加（273%）。这些结果提供了生理学证据，支持糖皮质激素诱导SULT1A1的生物学相关性。数据表明，类固醇治疗可诱导SULT1A1基因表达，从而增强米诺地尔的降压作用。
