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Association
of CYP3A6 Level with Incidence and Extent of Steroid Induced Osteonecrosis
in Rabbit
T
Masada, H Ohashi, Y Kaneshiro, K Takaoka
Department of Orthopaedic Surgery, Osaka City University Medical School,
Osaka, Japan
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-dose
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. The CYP3A6 level was modulated by inhibitory
(Itraconazole, 150mg p.o. twice a day for 3weeks) or inducing agent
(rifampicin, 100mg/kg i.p. in first 3days). Three weeks after modulation
of CYP3A6, steroid-induced osteonecrosis was generated by i.m. injection
of methylprednisolone (20mg/kg BW). Three weeks later, the animals
were sacrificed and bilateral femurs were excised and examined histologically
for bone and marrow necrosis. 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.
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 extention of steroid-induced bone necrosis,
and that induction of CYP3A6 might prevent steroid-induced bone necrosis.