Wright M C, Paine A J
DH Department of Toxicology, St Bartholomew's Hospital Medical College, London, UK.
Biochem Biophys Res Commun. 1994 Jun 15;201(2):973-9. doi: 10.1006/bbrc.1994.1797.
The specific binding of the archetypal cytochrome P450 3A subfamily (CYP3A) inducer dexamethasone is examined in microsomal fractions since rat and human liver CYP3A is induced by glucocorticoids through a mechanism which is apparently independent of the cytosolic glucocorticoid receptor. Dexamethasone binds in a specific and saturable manner to microsomes with an affinity constant (Kd) of 59 +/- 12.9 nM which compares to a Kd of 2.3 +/- 0.17 nM in cytosol. The total receptor concentrations ([LR]emax) in microsomes and cytosol are 9.5 +/- 1.67 pmols/mg protein and 410 +/- 167 fmol/mg protein respectively. The microsomal binding of dexamethasone is antagonised by several transcriptional and/or post-transcriptional CYP3A inducers with decreasing potency pregnenolone 16 alpha carbonitrile > metyrapone > phenobarbitone. Troleandomycin, which indirectly induces CYP3A1 in vivo and by protein stabilisation, does not antagonise the binding of dexamethasone in microsomes. The transcriptional and/or post-transcriptional induction of CYP3A may therefore be associated with the interaction of inducers with a microsomal protein.
由于大鼠和人类肝脏细胞色素P450 3A亚家族（CYP3A）可通过一种明显独立于胞质糖皮质激素受体的机制被糖皮质激素诱导，因此在微粒体组分中检测了原型CYP3A诱导剂地塞米松的特异性结合。地塞米松以特异性和可饱和的方式与微粒体结合，亲和常数（Kd）为59±12.9 nM，而在胞质溶胶中的Kd为2.3±0.17 nM。微粒体和胞质溶胶中的总受体浓度（[LR]emax）分别为9.5±1.67 pmol/mg蛋白质和410±167 fmol/mg蛋白质。几种转录和/或转录后CYP3A诱导剂可拮抗地塞米松与微粒体的结合，其效力递减顺序为孕烯醇酮16α-腈>美替拉酮>苯巴比妥。醋竹桃霉素在体内通过蛋白质稳定间接诱导CYP3A1，但不拮抗地塞米松与微粒体的结合。因此，CYP3A的转录和/或转录后诱导可能与诱导剂与微粒体蛋白的相互作用有关。
