Departments of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Drug Metab Rev. 2010 Feb;42(1):182-94. doi: 10.3109/03602530903208652.
Tamoxifen (TAM) is a selective estrogen-receptor modulator that is widely used in the prevention and treatment of estrogen-receptor-positive breast cancer. Its use has significantly contributed to a decline in breast cancer mortality, since breast cancer patients treated with TAM for 5 years exhibit a 30-50% reduction in both the rate of disease recurrence after 10 years of patient follow-up and in the occurrence of contralateral breast cancer. However, in patients treated with TAM, there is substantial interindividual variability in the development of resistance to TAM therapy and in the incidence of TAM-induced adverse events, including deep-vein thrombosis, hot flashes, and the development of endometrial cancer. Aromatase inhibitors (AIs) have emerged as a viable alternative to TAM, working by inhibiting aromatase activity and blocking estrone/estrodiol biosynthesis in postmenopausal women. The current third-generation AIs, anastrozole, exemestane, and letrozole, were used initially for the treatment of metastatic breast cancer, demonstrating similar or greater benefit but less toxicity, compared with TAM, and are now being employed as adjuvant treatment for early breast cancer in postmenopausal women. This article will focus on the UDP-glucuronosyltransferases, a family of metabolizing enzymes that play an important role in the deactivation and clearance of TAM, anastrazole, and exemestane, and how interindividual differences in these enzymes may play a role in patient response to these agents.
他莫昔芬（TAM）是一种选择性雌激素受体调节剂，广泛用于预防和治疗雌激素受体阳性乳腺癌。它的使用显著降低了乳腺癌死亡率，因为接受 TAM 治疗 5 年的乳腺癌患者在 10 年的患者随访后疾病复发率和对侧乳腺癌的发生都降低了 30-50%。然而，在接受 TAM 治疗的患者中，对 TAM 治疗的耐药性发展和 TAM 诱导的不良反应的发生率存在很大的个体差异，包括深静脉血栓形成、热潮红和子宫内膜癌的发生。芳香酶抑制剂（AIs）已成为 TAM 的可行替代品，通过抑制芳香酶活性和阻断绝经后妇女雌酮/雌二醇的生物合成。目前的第三代 AI，阿那曲唑、依西美坦和来曲唑，最初用于治疗转移性乳腺癌，与 TAM 相比具有相似或更大的益处但毒性更小，现在正在绝经后妇女的早期乳腺癌辅助治疗中使用。本文将重点介绍 UDP-葡糖醛酸基转移酶，这是一组代谢酶，在 TAM、阿那曲唑和依西美坦的失活和清除中发挥重要作用，以及这些酶的个体差异如何在患者对这些药物的反应中发挥作用。
