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首页> 外文期刊>Journal of orthopaedic research >Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid-induced osteonecrosis in a rabbit model.
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Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid-induced osteonecrosis in a rabbit model.

机译：肝细胞色素P4503A活性增加可降低在兔子模型中发生类固醇诱导的骨坏死的风险。

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摘要

Low hepatic cytochrome P4503A (CYP3A) activities might play an important role for inducing osteonecrosis of the femoral head (ONFH) by corticosteroids. However, the relationship between hepatic CYP3A activity and steroid-induced ONFH is unknown. We have examined the relationship between hepatic CYP3A activity and the inducibility of ONFH in a rabbit model. Sixty rabbits were divided into three groups. Hepatic CYP3A inducer (phenobarbital, group P; n = 15), inhibitor (itraconazole, group I; n = 15), or saline (group C, n = 30) was administrated for 3 weeks before intramuscular methylprednisolone. In groups P and I, hepatic CYP3A levels were measured by midazolam clearance before treatment (baseline) and before methylprednisolone injection. All animals were sacrificed 3 weeks after methylprednisolone injection and both femurs were harvested and examined histologically for osteonecrosis. Midazolam clearance was significantly increased and decreased, compared with baseline in groups P and I respectively (p< 0.0005, p < 0.002). The incidence of osteonecrosis in group P (33%) was significantly lower than in group I (100%) and group C (83%; p < 0.001 for both). The percentage necrotic area to whole bone marrow area on cross sections in group P (8.2 +/- 5.9%) was significantly lower than in group I (69.8 +/- 20.8%) and group C (51.5 +/- 30.7%; p < 0.005 for both). Hepatic CYP3A activity inversely correlated with the incidence of osteonecrosis and extent of the necrotic area caused by the same dose of corticosteroids, suggesting possible prevention of the steroid-induced osteonecrosis by reducing steroid dose in poor corticosteroid metabolizers.
机译：肝细胞色素P4503A（CYP3A）的低活性可能在皮质类固醇诱导股骨头坏死（ONFH）中起重要作用。然而，肝脏CYP3A活性与类固醇诱导的ONFH之间的关系尚不清楚。我们已经检查了肝CYP3A活性和兔模型中ONFH诱导性之间的关系。 60只兔子分为三组。在肌肉注射甲基强的松龙之前，给予肝CYP3A诱导剂（苯巴比妥，P组; n = 15），抑制剂（伊曲康唑，I组; n = 15）或生理盐水（C组，n = 30）3周。在P和I组中，在治疗前（基线）和甲基强的松龙注射前，通过咪达唑仑清除率测量肝CYP3A水平。注射甲基泼尼松龙3周后处死所有动物，并收集两个股骨并进行组织学检查以检查其骨坏死。与P组和I组的基线相比，咪达唑仑清除率显着提高和降低（p <0.0005，p <0.002）。 P组（33％）的骨坏死发生率显着低于I组（100％）和C组（83％;两者均p <0.001）。 P组横截面的坏死面积占整个骨髓面积的百分比（8.2 +/- 5.9％）显着低于I组（69.8 +/- 20.8％）和C组（51.5 +/- 30.7％; p两者均<0.005）。肝CYP3A活性与相同剂量的皮质类固醇引起的骨坏死的发生率和坏死面积的大小成反比，提示通过减少不良皮质类固醇代谢物中的类固醇剂量可以预防类固醇诱发的骨坏死。

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