On the mechanism of induction of microsomal cytochrome P450IVA1 and peroxisome proliferation in rat liver by clofibrate.
On the mechanism of induction of microsomal cytochrome P450IVA1 and peroxisome proliferation in rat liver by clofibrate.
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安妥明诱导大鼠肝脏微粒体细胞色素P450IVA1及过氧化物酶体增殖的机制研究
DOI：
10.1016/0006-2952(90)90594-b
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发表时间：
1990
影响因子：
5.8
通讯作者：
G. Gibson
中科院分区：
文献类型：
--
作者：
M. Milton;C. Elcombe;G. Gibson
研究了单次给药（250 mg/kg）对雄性Wistar大鼠肝脏微粒体和过氧化物酶体脂代谢酶诱导的时间过程。微粒体酶，细胞色素P450IVA1，显示出对氯贝特钠的双相反应，双相反应包括最初的小反应，在给药后约30分钟达到峰值，并在2小时后恢复到接近基线值。细胞色素P450IVA1的第二个主要诱导发生在给药后18 - 24小时。细胞色素P450IVA1的酶活性（月桂酸羟化酶）、免疫检测蛋白（使用特异性ELISA方法）和mRNA水平（使用2.1千碱基细胞色素P450IVA1 cDNA探针）均观察到这种双相现象。相反，过氧化物酶体脂肪酸β-氧化酶对氯贝特给药呈单相反应，在给药后约24小时达到峰值。因此，微粒体细胞色素P450IVA1在脂肪酸β-氧化过氧化物酶之前被诱导。另外还研究了环己亚胺对氯贝特诱导过氧化物酶体增殖的影响。预先给Wistar大鼠注射环己亚胺，消除了氯贝特酸盐依赖性诱导细胞色素P450IVA1和过氧化物酶体依赖性脂质代谢，并阻断了相应酶蛋白的合成。此外，环己亚胺还能抑制clofibrate依赖性的过氧化物酶体酰基辅酶a氧化酶mRNA的增加，但对诱导的细胞色素P450IVA1 mRNA水平没有影响，表明过氧化物酶体增殖现象存在蛋白质或酶依赖性。总的来说，我们的数据有力地证明微粒体细胞色素P450IVA1和过氧化物酶体脂肪酸β-氧化酶的调控是密切相关的，可能是通过细胞色素P450IVA1最初的、依赖于氯纤维素的调控。
The time course of induction of microsomal and peroxisomal lipid-metabolizing enzymes in male Wistar rat liver has been investigated following a single i.p. dose of clofibrate (250 mg/kg). The microsomal enzyme, cytochrome P450IVA1, demonstrated a biphasic response to sodium clofibrate administration, the biphasic response consisting of an initial small response, peaking at approximately 30 min post-dose and returning to near baseline values after 2 hr. A second major induction of cytochrome P450IVA1 occurred between 18 and 24 hr post-dose. This biphasic phenomenon for cytochrome P450IVA1 was observed for the enzyme activity (lauric acid hydroxylase), immunodetectable protein (using a specific ELISA method) and at the mRNA level (using a 2.1 kilobase cytochrome P450IVA1 cDNA probe). In contrast, peroxisomal fatty acid β-oxidation enzymes responded in a monophasic manner to clofibrate administration, peaking approximately 24 hr post-dose. Accordingly, microsomal cytochrome P450IVA1 was induced before the peroxisomal enzymes of fatty acid β-oxidation. The effect of cycloheximide on the induction of peroxisome proliferation by clofibrate was additionally investigated. The prior administration of cycloheximide to Wistar rats ablated the clofibrate-dependent induction of both cytochrome P450IVA1 and peroxisomal-dependent lipid metabolism and also blocked the corresponding synthesis of enzyme proteins. Cycloheximide additionally inhibited the clofibrate-dependent increase in peroxisomal acyl-CoA oxidase mRNA, but was without effect on the induced cytochrome P450IVA1 mRNA levels, indicating a protein or enzyme dependency for the phenomenon of peroxisome proliferation. Taken collectively, our data strongly argues that the regulation of microsomal cytochrome P450IVA1 and peroxisomal fatty acid β-oxidation enzymes are closely related, possibly through the initial, clofibrate-dependent regulation of cytochrome P450IVA1.
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DOI：
--
发表时间：
1982
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
White,BA;Bancroft,FC
通讯作者：
Bancroft,FC
影响因子：
15.9
作者：
TONSGARD, JH;GETZ, GS
通讯作者：
GETZ, GS
DOI：
10.1073/pnas.84.15.5242
发表时间：
1987-08-01
影响因子：
11.1
作者：
LALWANI, ND;ALVARES, K;REDDY, JK
通讯作者：
REDDY, JK
DOI：
10.1042/bj2410783
发表时间：
1987-02
期刊：
The Biochemical journal
影响因子：
--
作者：
J. Vamecq
通讯作者：
J. Vamecq