Low levels of steroid-metabolizing hepatic enzyme (cytochrome P450 3A) activity may elevate responsiveness to steroids and may increase risk of steroid-induced osteonecrosis even with low glucocorticoid dose.

Abstract

BACKGROUND: The main purpose of this study was to examine the relationships among osteonecrosis, steroid-metabolizing hepatic enzyme (cytochrome P450 3A; CYP3A) activity, and steroid dose to determine whether it is possible to prevent osteonecrosis in animals with low hepatic CYP3A activity by reducing exogenous steroid doses. METHODS: Japanese white rabbits (n = 103) were divided into three groups: a group with CYP3A activity induction (by intramuscular phenobarbital injection, n = 31), a group with CYP3A activity inhibition (by oral itraconazole administration, n = 30), and a control group (n = 42). Three weeks later, all rabbits received a methylprednisolone injection. Each group was divided into two subgroups by dosage of methylprednisolone (5 or 10 mg/kg body weight). Three weeks after methylprednisolone injections, the animals were killed and histological examination was performed to determine the incidences of osteonecrosis in the six subgroups. RESULTS: Incidence in the inhibition subgroup with 5 mg/kg steroid was higher than that in the induction subgroup receiving 10 mg/kg steroid. Thus, suppression of CYP3A activity significantly increased vulnerability to steroid-induced osteonecrosis, while increased CYP3A activity reduced this vulnerability. CONCLUSIONS: These findings suggest that low CYP3A activity may be vulnerable to the effect of steroids and increase risk of osteonecrosis, even with a low dose of steroid.