Dexamethasone induction of taxol metabolism in the rat.
Dexamethasone induction of taxol metabolism in the rat.
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发表时间：
1995-11
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通讯作者：
C. Anderson;J. Wang;G. Kumar;J. McMillan;U. Walle;T. Walle
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作者：
C. Anderson;J. Wang;G. Kumar;J. McMillan;U. Walle;T. Walle
本研究检查了地塞米松（DEX）（100 mg/kg/天，持续3天）对雄性和雌性Sprague-Dawley大鼠肝微粒体和肝细胞中[3 H]紫杉醇代谢的影响。在对照大鼠中，形成了两种同分异构的单羟基化代谢产物M1和M2。雄性动物中两种代谢物的形成量是雌性动物的2-3倍。DEX给药后，雄性动物的M1增加了2.6倍，雌性动物增加了6.5倍。这伴随着肝细胞色素P4503 A蛋白和睾酮6 β-羟基化的类似增加。仅在DEX给药动物中形成了三种额外的代谢产物（U1、U2和U3）。分离这些代谢物从大鼠肝细胞孵育物通过反相HPLC允许U2和U3的结构鉴定，使用串联MS。U3的质谱与紫杉醇的脱乙酰化一致，而U2的质谱与单羟基紫杉醇代谢物M2的脱乙酰化一致。U3的HPLC和MS数据与标准10-脱乙酰紫杉醇的数据的比较表明，脱乙酰化位点可能是紫杉烷环的4-位。初步观察表明，脱乙酰化是由DEX诱导的细胞色素P450引起的。
This study examined the effect of dexamethasone (DEX), 100 mg/kg/day for 3 days, on [3H]taxol metabolism in liver microsomes and hepatocytes of male and female Sprague-Dawley rats. In control rats, two isomeric monohydroxylated metabolites, M1 and M2, were formed. The formation of both metabolites was 2-3 times greater in the male than in the female animals. After DEX treatment, M1 increased 2.6-fold in the male animals and 6.5-fold in the female animals. This was accompanied by similar increases in hepatic cytochrome P4503A protein and testosterone 6 beta-hydroxylation. Three additional metabolites (U1, U2, and U3) were formed in the DEX-treated animals only. Isolation of these metabolites from rat hepatocyte incubates by reversed-phase HPLC permitted structure identification of U2 and U3, using tandem MS. The mass spectrum of U3 was consistent with deacetylation of taxol, whereas the mass spectrum of U2 was consistent with deacetylation of the monohydroxylated taxol metabolite M2. A comparison of HPLC and MS data for U3 with those of standard 10-deacetyltaxol suggested that the site of deacetylation might be the 4-position of the taxane ring. Preliminary observations indicate that the deacetylation is caused by a DEX-inducible cytochrome P450.