[Hepatic CYP3A activity in association with development of osteonecrosis of the femoral head].
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.
Kaneshiro
Yasunori
Y
Yodogawa Christian Hospital, Department of Orthopaedic surgery Osaka City University, Graduate school of medicine, Department of Orthopaedic surgery.
Takaoka
Kunio
K
D000305:Adrenal Cortex Hormones / Q000009:adverse effects* / Q000378:metabolism*; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D005271:Femur Head Necrosis / Q000209:etiology*; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000378:metabolism; D008875:Middle Aged; D012307:Risk Factors
D000305:Adrenal Cortex Hormones; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam