Kaneshiro Yasunori, Takaoka Kunio
Yodogawa Christian Hospital, Department of Orthopaedic surgery Osaka City University, Graduate school of medicine, Department of Orthopaedic surgery.
Clin Calcium. 2007 Jun;17(6):902-9.
Osteonecrosis of the femoral head (ONFH) is one of the major side effects of corticosteroid therapy. Since corticosteroids are metabolized by hepatic cytochrome P450 3A (CYP3A), a low endogenous activity of this enzyme may exert excessive or toxic effect to bone and contribute to development of ONFH. To test this hypothesis, we measured hepatic CYP3A activity in 130 patients (26 with steroid-induced ONFH, 29 alcohol-related ONFH, and 75 normal controls without corticosteroid therapy and ONFH) by measuring the clearance of midazolam (MDZ) , a substrate specific to CYP3A, and found that MDZ clearance in steroid-induced ONFH patients was significantly retarded when compared with that in controls or alcohol-related ONFH patients. Multivariate analysis revealed that only MDZ clearance was significantly related with steroid-induced ONFH and the patients with low MDZ clearance due to low hepatic CYP3A activity provided 9-fold greater risk for steroid-induced ONFH. Therefore, low hepatic CYP3A activity would be significant risk factor to the onset of steroid-induced ONFH.
股骨头坏死（ONFH）是皮质类固醇治疗的主要副作用之一。由于皮质类固醇由肝细胞色素P450 3A（CYP3A）代谢，该酶的低内源性活性可能对骨骼产生过度或毒性作用，并导致ONFH的发生。为了验证这一假设，我们通过测量CYP3A特异性底物咪达唑仑（MDZ）的清除率，对130例患者（26例类固醇诱导的ONFH患者、29例酒精相关的ONFH患者以及75例未接受皮质类固醇治疗且无ONFH的正常对照）的肝脏CYP3A活性进行了测量，发现与对照组或酒精相关的ONFH患者相比，类固醇诱导的ONFH患者的MDZ清除率明显延迟。多变量分析显示，只有MDZ清除率与类固醇诱导的ONFH显著相关，并且由于肝脏CYP3A活性低而导致MDZ清除率低的患者发生类固醇诱导的ONFH的风险高出9倍。因此，肝脏CYP3A活性低将是类固醇诱导的ONFH发病的重要危险因素。
