Yang Fan, Sharma Sangeeta Shrestha, Bureik Matthias, Parr Maria Kristina
Pharmaceutical and Medicinal Chemistry (Pharmaceutical Analyses), Institute of Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
Curr Issues Mol Biol. 2023 Aug 26;45(9):7130-7146. doi: 10.3390/cimb45090451.
Cytochromes P450 (CYP) and UDP-glucuronosyltransferases (UGT) are two enzyme families that play an important role in drug metabolism, catalyzing either the functionalization or glucuronidation of xenobiotics. However, their mutual interactions are poorly understood. In this study, the functional interactions of human CYP2D6 with four human UGTs (UGT1A7, UGT1A8, UGT1A9, and UGT2A1) were investigated using our previously established co-expression model system in the fission yeast . The substrate employed was propranolol because it is well metabolized by CYP2D6. Moreover, the CYP2D6 metabolite 4-hydroxypropranolol is a known substrate for the four UGTs included in this study. Co-expression of either UGT1A7, UGT1A8, or UGT1A9 was found to increase the activity of CYP2D6 by a factor of 3.3, 2.1 or 2.8, respectively, for the conversion of propranolol to 4-hydroxypropranolol. In contrast, UGT2A1 co-expression did not change CYP2D6 activity. On the other hand, the activities of all four UGTs were completely suppressed by co-expression of CYP2D6. This data corroborates our previous report that CYP2D6 is involved in functional CYP-UGT interactions and suggest that such interactions can contribute to both adverse drug reactions and changes in drug efficacy.
细胞色素P450（CYP）和尿苷二磷酸葡萄糖醛酸基转移酶（UGT）是在药物代谢中起重要作用的两个酶家族，它们催化外源性物质的官能化或葡萄糖醛酸化反应。然而，它们之间的相互作用却鲜为人知。在本研究中，利用我们之前在裂殖酵母中建立的共表达模型系统，研究了人CYP2D6与四种人UGT（UGT1A7、UGT1A8、UGT1A9和UGT2A1）之间的功能相互作用。所使用的底物是普萘洛尔，因为它能被CYP2D6很好地代谢。此外，CYP2D6的代谢产物4-羟基普萘洛尔是本研究中所包含的四种UGT的已知底物。结果发现，共表达UGT1A7、UGT1A8或UGT1A9时，普萘洛尔转化为4-羟基普萘洛尔的过程中，CYP2D6的活性分别增加了3.3倍、2.1倍或2.8倍。相比之下，共表达UGT2A1并没有改变CYP2D6的活性。另一方面，CYP2D6的共表达完全抑制了所有四种UGT的活性。这些数据证实了我们之前的报道，即CYP2D6参与了功能性CYP-UGT相互作用，并表明这种相互作用可能导致药物不良反应和药物疗效的改变。
