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ASSOCIATION OF CYP3A6 LEVEL WITH INCIDENCE AND EXTENT OF STEROID INDUCED OSTEONECROSIS IN RABBIT



Abstract

Introduction: Based on epidemiological results, steroid (glucocorticoid) hormone is accepted as a major causative agent of osteonecrosis, though its pathomechanism is not elucidated. However, not all patients who receive high doses of steroid develop osteonecrosis. This fact suggests risk factor(s) for steroid-induced osteonecrosis. In order to identify such risk factors, the association of CYP3A6 (a major enzyme metabolizing glucocorticoid in rabbit) level with the incidence and extent of osteonecrosis in a rabbit model was determined.

Materials and Methods: In this rabbit model, the CYP3A6 level was modulated by an inhibitory (Itraconazole, 150mg p.o. twice a day for 3 weeks) or inducing agent (rifampicin, 100mg/kg i.p. in first 3 days). Three weeks after modulation of CYP3A6, steroid-induced osteonecrosis was generated by i.m. injection of methyl-prednisolone (20mg/kg BW). Three weeks later, the animals were sacrificed and bilateral femurs were excised and examined histologically for bone and marrow necrosis.

Results: In control animals without modulation of CYP3A6, focal and/or extensive necrosis was noted in 5 of 7 animals. In Itraconazole-treated animals, all of 5 animals revealed extensive necrosis in femoral bone marrow. In rifampicin- treated animals, incidence of necrosis was similar to that of controls but necrotic foci were significantly smaller than those in controls.

Discussion: These experimental results indicated that low level of steroid-metabolizing enzyme CYP3A6 (CYP3A4 in humans) at the time of steroid treatment might be a risk factor for extension of steroid-induced bone necrosis, and that induction of CYP3A6 might prevent steroid-induced bone necrosis.

The abstracts were prepared by Michael A. Mont, M.D. and Lynne C. Jones, Ph.D. Correspondence should be addressed to L. Jones at Good Samaritan Prof. Bldg., Suite 201, 5601 Loch Raven Blvd., Baltimore, MD 21239