Coordinate up-regulation of CYP1A1 and heme oxygenase-1 (HO-1) expression and modulation of delta-aminolevulinic acid synthase and tryptophan pyrrolase activities in pyridine-treated rats.
Coordinate up-regulation of CYP1A1 and heme oxygenase-1 (HO-1) expression and modulation of delta-aminolevulinic acid synthase and tryptophan pyrrolase activities in pyridine-treated rats.
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在吡啶处理的大鼠中协调 CYP1A1 和血红素加氧酶-1 (HO-1) 表达的上调以及 δ-氨基乙酰丙酸合酶和色氨酸吡咯酶活性的调节。
DOI：
10.1016/s0006-2952(99)00137-9
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发表时间：
1999
影响因子：
5.8
通讯作者：
Fung,J
中科院分区：
文献类型：
--
作者：
Iba,MM;Alam,J;Touchard,C;Thomas,PE;Ghosal,A;Fung,J
为探讨与吡啶诱导细胞色素P450表达相关的血红素代谢的变化，我们比较了1 0 0 mg/kg或1 5 0 mg/kg腹腔注射大鼠组织中细胞色素P4 5 0的表达与(1)血红素加氧酶-1(HO-1)的表达(EC 1.14.99.3)、(2)δ-氨基酮丙酸合成酶(ALAS)的活性(EC 2.3.1.37)和(3)色氨酸焦解酶(TPO)的血红素饱和度(EC 1.13.11.11)的时间进程。剂量的吡啶。肝、肾和肺中均有HO-1和CYP1A1基因的表达，但肝和肺中HO-1mRNA和蛋白的表达先于并平行于肝和肺中的表达，而肾脏则不表达。在所检测的所有组织中，CYP1A1 mRNA的诱导表达在9-12小时内达到峰值，并在24小时时恢复到对照水平，而HO-1mRNA的诱导在肺和肝脏中持续48小时。与一过性的细胞色素P450 1A1基因表达上调相反，微粒体细胞色素P1A1蛋白的增加在三种组织中都持续存在。类似于HO-1表达的诱导，吡啶处理可在肾脏、肺和肝脏刺激脂质过氧化，但在肝脏和肺的刺激比在肾脏更持久。肝脏细胞色素P4501A1或细胞色素P1A2活性增加之前，HO-1和ALAS活性增加。吡啶处理对肝脏TPO的血红素饱和度有负性调节作用。这些结果表明，吡啶协同刺激了血红素的合成、利用和降解，提示这些血红素代谢的改变可能参与了吡啶诱导的细胞色素P1A1的表达。
To determine the changes in heme metabolism associated with induction of cytochrome P450 expression by pyridine, we compared the time course of CYP1A expression with the time course of (i) expression of heme oxygenase-1 (HO-1) (EC 1.14.99.3), (ii) activity of δ-aminolevulinic acid synthetase (ALAS) (EC 2.3.1.37), and (iii) heme saturation of tryptophan pyrrolase (TPO) (EC 1.13.11.11) in tissues of rats administered a single 100 or 150 mg/kg i.p. dose of pyridine. Both mRNA and protein of HO-1 and CYP1A1 were induced in the liver, kidney, and lung, with the induction of HO-1 mRNA preceding and paralleling that of CYP1A1 mRNA in the liver and lung but not kidney. Induction of CYP1A1 mRNA expression peaked within 9–12 hr and returned to control levels by 24 hr in all tissues examined, whereas induction of HO-1 mRNA expression was sustained for 48 hr in the lung and liver. In contrast to the transient up-regulation of CYP1A1 mRNA, increased microsomal CYP1A1 protein was sustained in all three tissues. Similar to the induction of HO-1 expression, lipid peroxidation was stimulated by pyridine treatment in the kidney, lung, and liver, but with the stimulation being more persistent in the liver and lung than in the kidney. Increased hepatic CYP1A1 or CYP1A2 activity was preceded by increased activities of HO-1 and ALAS. Pyridine treatment negatively modulated heme saturation of hepatic TPO. The findings indicate that pyridine stimulates the synthesis, utilization, and degradation of heme in a coordinate manner, and suggest that these alterations in heme metabolism may contribute to CYP1A1 induction by pyridine.