Kurogi Katsuhisa, Chepak Andriy, Hanrahan Michael T, Liu Ming-Yih, Sakakibara Yoichi, Suiko Masahito, Liu Ming-Cheh
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Toledo, OH 43614, USA.
National Synchrotron Radiation Research Center, Hsinchu, Taiwan, ROC.
Eur J Pharm Sci. 2014 Oct 1;62:40-8. doi: 10.1016/j.ejps.2014.05.003. Epub 2014 May 14.
The current study was designed to examine the sulfation of eight opioid drugs, morphine, hydromorphone, oxymorphone, butorphanol, nalbuphine, levorphanol, nalorphine, and naltrexone, in HepG2 human hepatoma cells and human organ samples (lung, liver, kidney, and small intestine) and to identify the human SULT(s) responsible for their sulfation. Analysis of the spent media of HepG2 cells, metabolically labeled with [35S]sulfate in the presence of each of the eight opioid drugs, showed the generation and release of corresponding [35S]sulfated derivatives. Five of the eight opioid drugs, hydromorphone, oxymorphone, butorphanol, nalorphine, and naltrexone, appeared to be more strongly sulfated in HepG2 cells than were the other three, morphine, nalbuphine, and levorphanol. Differential sulfating activities toward the opioid drugs were detected in cytosol or S9 fractions of human lung, liver, small intestine, and kidney, with the highest activities being found for the liver sample. A systematic analysis using eleven known human SULTs and kinetic experiment revealed SULT1A1 as the major responsible SULTs for the sulfation of oxymorphone, nalbuphine, nalorphine, and naltrexone, SULT1A3 for the sulfation of morphine and hydromorphone, and SULT2A1 for the sulfation of butorphanol and levorphanol. Collectively, the results obtained imply that sulfation may play a significant role in the metabolism of the tested opioid drugs in vivo.
本研究旨在检测吗啡、氢吗啡酮、羟吗啡酮、布托啡诺、纳布啡、左啡诺、纳洛啡和纳曲酮这八种阿片类药物在HepG2人肝癌细胞和人体器官样本（肺、肝、肾和小肠）中的硫酸化情况，并确定负责其硫酸化的人源硫酸转移酶（SULT）。在八种阿片类药物各自存在的情况下，用[35S]硫酸盐对HepG2细胞进行代谢标记，分析其用过的培养基，结果显示产生并释放了相应的[35S]硫酸化衍生物。八种阿片类药物中的五种，即氢吗啡酮、羟吗啡酮、布托啡诺、纳洛啡和纳曲酮，在HepG2细胞中的硫酸化程度似乎比其他三种，即吗啡、纳布啡和左啡诺更强。在人肺、肝、小肠和肾的胞质溶胶或S9组分中检测到对阿片类药物的不同硫酸化活性，其中肝脏样本的活性最高。使用11种已知的人源SULT进行系统分析和动力学实验表明，SULT1A1是羟吗啡酮、纳布啡、纳洛啡和纳曲酮硫酸化的主要负责SULT，SULT1A3是吗啡和氢吗啡酮硫酸化的负责SULT，SULT2A1是布托啡诺和左啡诺硫酸化的负责SULT。总体而言，所得结果表明硫酸化可能在体内受试阿片类药物的代谢中起重要作用。
