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.
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.
Tokuhara
Yoshio
Y
Department of Orthopaedic Surgery, Hanwa Joint Reconstruction Center Hospital, Sakai, Japan.
Wakitani
Shigeyuki
S
Oda
Yutaka
Y
Kaneshiro
Yasunori
Y
Masada
Toshiaki
T
Kim
Mitsunari
M
Kadoya
Yoshinori
Y
Azuma
Takashi
T
Takaoka
Kunio
K
D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008775:Methylprednisolone / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism*; D010020:Osteonecrosis / Q000139:chemically induced*; D011817:Rabbits; D012307:Risk Factors
D005938:Glucocorticoids; D051544:Cytochrome P-450 CYP3A; D008775:Methylprednisolone