Sulfation of buprenorphine, pentazocine, and naloxone by human cytosolic sulfotransferases.
Sulfation of buprenorphine, pentazocine, and naloxone by human cytosolic sulfotransferases.
复制标题
DOI：
10.2174/187231212804096673
复制
发表时间：
2012-05
影响因子：
--
通讯作者：
K. Kurogi;Mei Chen;Yoonjung Lee;Bo Shi;Ten Yan;Ming-yih Liu;Y. Sakakibara;M. Suiko;Ming-Cheh Liu
中科院分区：
文献类型：
--
作者：
K. Kurogi;Mei Chen;Yoonjung Lee;Bo Shi;Ten Yan;Ming-yih Liu;Y. Sakakibara;M. Suiko;Ming-Cheh Liu
丁丙诺啡、五氮唑卡因和纳洛酮是用于治疗疼痛和阿片依赖或过量的阿片类药物。由胞液磺基转移酶(Sults)催化的硫酸盐化参与了包括药物化合物在内的多种外源物质的代谢。阿片类药物的硫酸盐化还没有得到很好的研究。本研究旨在检测三种阿片类药物丁丙诺啡、五唑酮和纳洛酮在HepG2人肝癌细胞中的硫化作用，并确定导致它们硫化的人类结果(S)。在三种阿片类药物存在下，用[(35)S]硫酸盐代谢性标记的HepG2细胞的培养上清液分析表明，它们的[(35)S]硫酸盐衍生物的产生和释放。对11个已知的人类硫磺进行的系统分析显示，SULT1A3和SULT2A1分别是五唑类和丁丙诺啡硫化的主要负责硫化物；而另外三个硫磺，SULT1A1，SULT1A2和SULT1C4，能够硫化纳洛酮。以这些阿片类药物的组合为底物的酶分析表明，纳洛酮对丁丙诺啡和五唑酮的硫化反应有明显的抑制作用。在人肺、肝、肾和小肠的胞浆或S9组分中检测到对这三种阿片类药物的不同硫酸盐化活性。综上所述，这些结果表明，硫化作用可能在丁丙诺啡、五唑酮和纳洛酮的体内代谢中发挥作用。
Buprenorphine, pentazocine, and naloxone are opioid drugs used for the treatment of pain and opioid dependence or overdose. Sulfation as catalyzed by the cytosolic sulfotransferases (SULTs) is involved in the metabolism of a variety of xenobiotics including drug compounds. Sulfation of opioid drugs has not been well investigated. The current study was designed to examine the sulfation of three opioid drugs, buprenorphine, pentazocine, and naloxone, in HepG2 human hepatoma cells and to identify the human SULT(s) responsible for their sulfation. Analysis of the spent media of HepG2 cells, metabolically labeled with [(35)S]sulfate in the presence of each of the three opioid drugs, showed the generation and release of their [(35)S]sulfated derivatives. A systematic analysis using eleven known human SULTs revealed SULT1A3 and SULT2A1 as the major responsible SULTs for the sulfation of, respectively, pentazocine and buprenorphine; whereas three other SULTs, SULT1A1, SULT1A2, and SULT1C4, were capable of sulfating naloxone. Enzymatic assays using combinations of these opioid drugs as substrates showed significant inhibitory effects in the sulfation of buprenorphine and pentazocine by naloxone. Differential sulfating activities toward the three opioid drugs were detected in cytosol or S9 fractions of human lung, liver, kidney, and small intestine. Collectively, these results imply that sulfation may play a role in the metabolism of buprenorphine, pentazocine, and naloxone in vivo.