Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin 9016, New Zealand.
Science for Communities, Christchurch Science Centre, Christchurch 8041, New Zealand.
Int J Mol Sci. 2023 May 29;24(11):9424. doi: 10.3390/ijms24119424.
The potential to improve the effectiveness and efficiency of potential oestrogen-based oral contraceptives (fertility control) for possums was investigated by comparing the inhibitory potential of hepatic CYP3A and UGT2B catalytic activity using a selected compound library (CYP450 inhibitor-based compounds) in possums to that of three other species (mouse, avian, and human). The results showed higher CYP3A protein levels in possum liver microsomes compared to other test species (up to a 4-fold difference). Moreover, possum liver microsomes had significantly higher basal -nitrophenol glucuronidation activity than other test species (up to an 8-fold difference). However, no CYP450 inhibitor-based compounds significantly decreased the catalytic activity of possum CYP3A and UGT2B below the estimated IC and 2-fold IC values and were therefore not considered to be potent inhibitors of these enzymes. However, compounds such as isosilybin (65%), ketoconazole (72%), and fluconazole (74%) showed reduced UGT2B glucuronidation activity in possums, mainly at 2-fold IC values compared to the control ( < 0.05). Given the structural features of these compounds, these results could provide opportunities for future compound screening. More importantly, however, this study provided preliminary evidence that the basal activity and protein content of two major drug-metabolising enzymes differ in possums compared to other test species, suggesting that this could be further exploited to reach the ultimate goal: a potential target-specific fertility control for possums in New Zealand.
研究人员通过比较选定的化合物文库（基于 CYP450 抑制剂的化合物）对负鼠肝脏 CYP3A 和 UGT2B 催化活性的抑制潜力，以及其他三个物种（鼠、禽类和人类），研究了提高基于雌激素的潜在口服避孕药（生育控制）对负鼠有效性和效率的潜力。结果表明，与其他测试物种相比，负鼠肝微粒体中的 CYP3A 蛋白水平更高（高达 4 倍差异）。此外，负鼠肝微粒体的基础 - 硝基苯酚葡萄糖醛酸化活性明显高于其他测试物种（高达 8 倍差异）。然而，没有基于 CYP450 抑制剂的化合物能显著降低负鼠 CYP3A 和 UGT2B 的催化活性，使其低于估计的 IC 和 2 倍 IC 值，因此不被认为是这些酶的有效抑制剂。然而，某些化合物，如异甘草素（65%）、酮康唑（72%）和氟康唑（74%），在负鼠中显示出 UGT2B 葡萄糖醛酸化活性降低，主要在 2 倍 IC 值时与对照相比（<0.05）。鉴于这些化合物的结构特征，这些结果为未来的化合物筛选提供了机会。然而，更重要的是，这项研究初步表明，与其他测试物种相比，两种主要药物代谢酶在负鼠中的基础活性和蛋白含量存在差异，这表明这可能进一步被利用，以达到最终目标：在新西兰对负鼠进行潜在的靶向生育控制。
