The effects of P gp and CYP450 modulated by rifampicin on the steroid induced osteonecrosis of the femoral head
This study investigated the effects of rifampicin modulated P glycoprotein (P gp) and cytochrome P450 (CYP450) activity on the development of steroid induced osteonecrosis of the femoral head. Thirty two rabbits were equally divided into four groups: control group, oral administration group, intramuscular injection group, and local release group, in which rifampicin loaded artificial bone graft was implanted in the left femur cavity and blank bone graft was implanted in the right femur cavity. Dexamethasone was given 1 week after rifampicin administration. Peripheral P gp activity and hepatic CYP450 content were investigated 4 weeks later. Hematoxylin and eosin, Massson, and tetracycline fluorescence staining of the femoral head were compared. In vitro, the effects of intracellular dexamethasone concentration modulated by P gp on osteoprotegerin (OPG)/receptor activator of nuclear factor kB ligand (RANKL) expression and differentiation of mesenchymal stem cells were further investigated. Peripheral P gp activity and hepatic CYP450 content in the oral administration group and the intramuscular injection group were significantly higher than those in the local release group. P gp activity of mesenchymal stem cells in rifampicin implanted femoral head was significantly higher than that in the blank control. Histological study showed that rifampicin could prevent steroid induced bone loss and lipid formation, and promote new bone formation and maturation. In vitro study confirmed that intracellular dexamethasone concentration modulated by P gp could influence the OPG/RANKL ratio and the differentiation of mesenchymal stem cells. Enhanced levels of peripheral P gp and hepatic CYP450 can reduce the incidence of steroid induced osteonecrosis of the femoral head. P gp activity locally enhanced by rifampicin decreases the intracellular steroid concentration, but rifampicin does not have significant effects on peripheral P gp and hepatic CYP450.
Journal of Bone and Mineral Metabolism