Wang Min, Ebmeier Christopher C, Olin John R, Anderson Robert J
Section of Endocrinology, Veterans Affairs Medical Center, Creighton University Medical Center, Omaha, NE 68105, USA.
Steroids. 2006 May;71(5):343-51. doi: 10.1016/j.steroids.2005.11.003. Epub 2005 Dec 19.
Sulfation is a major pathway in humans for the biotransformation of steroid hormones and structurally related therapeutic agents. Tibolone is a synthetic steroid used for the treatment for climacteric symptoms and postmenopausal osteoporosis. Sulfation inactivates the hydroxylated metabolites, 3alpha-hydroxytibolone (3alpha-OH-tibolone) and 3beta-hydroxytibolone (3beta-OH-tibolone), and contributes to the regulation of tissue responses to tibolone. We detected SULT1A1, SULT1A3, SULT1E1 and SULT2A1 mRNA expression by RT-PCR in postmenopausal liver and small intestine. Liver pool (n=5) SULT activities measured with tibolone substrates reflected COS-1 expressed SULT2A1 and SULT1E1 activities. Liver SULT2A1 activity (1.8 +/- 0.3 units/mg protein, n = 8, mean +/- SEM), and activities with 3alpha-OH-tibolone (0.6 +/- 0.1, n = 8) and 3beta-OH-tibolone (0.9 +/- 0.2, n = 8) were higher than SULT1E1 activities (<0.05, n = 10). SULT1E1 activities were low or not detected in many samples. Mean small intestinal activities were 0.03 +/- 0.01 with 3alpha-OH-tibolone and 0.04 +/- 0.01 with 3beta-OH-tibolone (n = 3). In conclusion, SULT2A1 is the major endogenous enzyme responsible for sulfation of the tibolone metabolites in human postmenopausal tissues. The results support the occurrence of pre-receptor enzymatic regulation of hydroxytibolone metabolites and prompt further investigation of the tissue-selective regulation of tibolone effects.
硫酸化是人体中甾体激素和结构相关治疗药物生物转化的主要途径。替勃龙是一种合成甾体，用于治疗更年期症状和绝经后骨质疏松症。硫酸化使羟基化代谢产物3α-羟基替勃龙（3α-OH-替勃龙）和3β-羟基替勃龙（3β-OH-替勃龙）失活，并有助于调节组织对替勃龙的反应。我们通过逆转录聚合酶链反应（RT-PCR）检测了绝经后肝脏和小肠中磺基转移酶1A1（SULT1A1）、磺基转移酶1A3（SULT1A3）、磺基转移酶1E1（SULT1E1）和磺基转移酶2A1（SULT2A1）的mRNA表达。用替勃龙底物测量的肝脏样本（n = 5）的SULT活性反映了COS-1细胞表达的SULT2A1和SULT1E1活性。肝脏SULT2A1活性（1.8±0.3单位/毫克蛋白，n = 8，平均值±标准误）以及对3α-OH-替勃龙的活性（0.6±0.1，n = 8）和对3β-OH-替勃龙的活性（0.9±0.2，n = 8）高于SULT1E1活性（<0.05，n = 10）。在许多样本中，SULT1E1活性较低或未检测到。小肠对3α-OH-替勃龙的平均活性为0.03±0.01，对3β-OH-替勃龙的平均活性为0.04±0.01（n = 3）。总之，SULT2A1是负责绝经后人体组织中替勃龙代谢产物硫酸化的主要内源性酶。这些结果支持了羟基替勃龙代谢产物的受体前酶促调节的存在，并促使对替勃龙作用的组织选择性调节进行进一步研究。
