Luo Lijun, Zhou Chunyang, Hui Ying, Kurogi Katsuhisa, Sakakibara Yoichi, Suiko Masahito, Liu Ming-Cheh
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, OH 43614, USA; School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan, China.
Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Health Science Campus, Toledo, OH 43614, USA; Department of Obstetrics and Gynecology, Beijing Hospital, Beijing 100730, China.
Drug Metab Pharmacokinet. 2016 Apr;31(2):163-6. doi: 10.1016/j.dmpk.2016.01.003. Epub 2016 Jan 22.
Doxorubicin, an anthracycline, has been reported to be excreted in sulfate conjugated form. The current study aimed to identify the human cytosolic sulfotransferase(s) (SULT(s)) that is(are) capable of sulfating doxorubicin and its analog epirubicin, and to verify whether sulfation of doxorubicin and epirubicin may occur under metabolic conditions. A systematic analysis of thirteen known human SULTs, previously cloned, expressed, and purified, revealed SULT1C4 as the only human SULT capable of sulfating doxorubicin and epirubicin. Cultured HepG2 human hepatoma cells and Caco-2 human colon carcinoma cells were labeled with [(35)S]sulfate in the presence of different concentrations of doxorubicin or epirubicin. Analysis of spent labeling media showed the generation and release of [(35)S]sulfated doxorubicin and epirubicin by HepG2 cells and Caco-2 cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed the expression of SULT1C4 in both HepG2 cells and Caco-2 cells. These results provided a molecular basis underlying the previous finding that sulfate-conjugated doxorubicin was excreted in the urine of patients treated with doxorubicin.
阿霉素是一种蒽环类药物，据报道它以硫酸共轭形式排泄。当前的研究旨在鉴定能够使阿霉素及其类似物表柔比星硫酸化的人胞质磺基转移酶（SULT），并验证在代谢条件下阿霉素和表柔比星是否会发生硫酸化。对先前克隆、表达和纯化的13种已知人SULT进行系统分析，结果显示SULT1C4是唯一能够使阿霉素和表柔比星硫酸化的人SULT。在不同浓度的阿霉素或表柔比星存在的情况下，用[³⁵S]硫酸盐标记培养的人肝癌HepG2细胞和人结肠癌Caco-2细胞。对用过的标记培养基进行分析，结果显示HepG2细胞和Caco-2细胞生成并释放了[³⁵S]硫酸化的阿霉素和表柔比星。逆转录-聚合酶链反应（RT-PCR）分析显示HepG2细胞和Caco-2细胞中均有SULT1C4表达。这些结果为先前的发现提供了分子基础，即在用阿霉素治疗的患者尿液中排泄有硫酸共轭的阿霉素。
