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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia
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Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia

机译：通过体内和体外CYP3A4诱导增强25-羟基维生素D3的肝脏4-羟基化作用：对药物诱导的骨软化症的影响

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Long-term therapy with certain drugs, especially cytochrome P450 (P450; CYP)-inducing agents, confers an increased risk of osteomalacia that is attributed to vitamin D deficiency. Human CYP24A1, CYP3A4, and CYP27B1 catalyze the inactivation and activation of vitamin D and have been implicated in the adverse drug response. In this study, the inducibility of these enzymes and monohydroxylation of 25-hydroxyvitamin D3 (25OHD3) were evaluated after exposure to P450-inducing drugs. With human hepatocytes, treatment with phenobarbital, hyperforin, carbamazepine, and rifampin significantly increased the levels of CYP3A4, but not CYP24A1 or CYP27B1 mRNA. In addition, rifampin pretreatment resulted in an 8-fold increase in formation of the major metabolite of 25OHD3, 4β,25(OH)2D 3. This inductive effect was blocked by the addition of 6′,7′-dihydroxybergamottin, a selective CYP3A4 inhibitor. With human renal proximal tubular HK-2 cells, treatment with the same inducers did not alter CYP3A4, CYP24A1, or CYP27B1 expression. 24R,25(OH)2D 3 was the predominant monohydroxy metabolite produced from 25OHD 3, but its formation was unaffected by the inducers. With healthy volunteers, the mean plasma concentration of 4β,25(OH)2D 3 was increased 60% (p 0.01) after short-term rifampin administration. This was accompanied by a statistically significant reduction in plasma 1α,25(OH)2D3 (-10%; p = 0.03), and a nonsignificant change in 24R,25(OH)2D3 (-8%; p = 0.09) levels. Further analysis revealed a negative correlation between the increase in 4β,25(OH)2D3 and decrease in 1α,25(OH) 2D3 levels. Examination of the plasma monohydroxy metabolite/25OHD3 ratios indicated selective induction of the CYP3A4-dependent 4β-hydroxylation pathway of 25OHD3 elimination. These results suggest that induction of hepatic CYP3A4 may be important in the etiology of drug-induced osteomalacia.
机译：长期使用某些药物，尤其是细胞色素P450（P450; CYP）诱导剂进行长期治疗，会由于维生素D缺乏而导致骨软化症的风险增加。人CYP24A1，CYP3A4和CYP27B1催化维生素D的失活和激活，并与药物不良反应有关。在这项研究中，这些酶的诱导性和25-羟基维生素D3（25OHD3）的单羟基化在暴露于P450诱导药物后进行了评估。对于人肝细胞，用苯巴比妥，hyperforin，卡马西平和利福平治疗可显着增加CYP3A4的水平，但不增加CYP24A1或CYP27B1 mRNA的水平。此外，利福平预处理导致25OHD3、4β，25（OH）2D 3的主要代谢物形成增加8倍。这种诱导作用被6'，7'-二羟基香柠檬素（一种选择性CYP3A4）的加入所阻断。抑制剂。对于人肾近端肾小管HK-2细胞，使用相同的诱导剂治疗不会改变CYP3A4，CYP24A1或CYP27B1的表达。 24R，25（OH）2D 3是由25OHD 3产生的主要单羟基代谢产物，但其形成不受诱导剂的影响。对于健康志愿者，短期给予利福平后，平均血浆4β，25（OH）2D 3浓度增加了60％（p <0.01）。这伴随着血浆1α，25（OH）2D3（-10％; p = 0.03）的统计学显着降低，以及24R，25（OH）2D3（-8％; p = 0.09）水平无显着变化。进一步的分析显示4β，25（OH）2D3的增加与1α，25（OH）2D3的减少之间存在负相关。血浆单羟基代谢物/ 25OHD3比率的检查表明选择性诱导25OHD3消除的CYP3A4依赖性4β-羟基化途径。这些结果提示肝CYP3A4的诱导在药物诱导的骨软化病的病因学中可能是重要的。

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