Induction of hepatic heme oxygenase activity by bromobenzene.
Induction of hepatic heme oxygenase activity by bromobenzene.
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溴苯诱导肝血红素加氧酶活性。
DOI：
10.1016/0003-9861(79)90564-2
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发表时间：
1979
影响因子：
3.9
通讯作者：
N. Elshourbagy
中科院分区：
文献类型：
--
作者：
P. Guzelian;N. Elshourbagy
肝血红素加氧酶是一种在体外将血红素转化为一氧化碳和胆色素的酶，它不仅能被血红素诱导，而且也能被大剂量的非血红素物质如激素、内毒素和重金属离子诱导。当我们给予大鼠单次肝毒性剂量的烯丙醇、乙醇、对乙酰氨基酚、呋塞米或内毒素时，20小时后肝脏血红素加氧酶活性适度升高（2 - 5倍）。与此相反，溴苯（5 mmol/kg）的管理诱导血红素加氧酶在肝脏中的平均15倍，20小时后，但没有影响的酶在肾脏或脾脏。血红素加氧酶的变化伴随着细胞色素P-450浓度的损失，在5-δ-氨基[14 C]乙酰丙酸标记的大鼠中，肝脏[14 C]血红素降解为14 CO的速率增加。溴苯诱导血红素加氧酶被蛋白质合成抑制剂放线菌酮阻断，但不被RNA合成抑制剂放线菌素D阻断。这表明溴苯在翻译步骤促进了新酶的合成。亚毒性剂量的溴苯（小于1 mmol/kg）的血红素加氧酶的诱导比例更大。此外，当用SKF-525 A、3-甲基胆蒽或半胱氨酸（补充肝脏巯基含量）预处理大鼠阻断溴苯肝毒性时，或当用苯巴比妥或马来酸二乙酯（消耗肝脏谷胱甘肽）预处理增强肝毒性时，酶的诱导不受影响。这些数据表明，与诱导血红素加氧酶的溴苯，既不是肝细胞坏死，也不改变肝巯基代谢是必不可少的。后一个特征不同于金属离子对酶的诱导，其中含巯基成分的耗尽被认为是必不可少的。我们的结论是，溴苯是一种新的诱导血红素加氧酶活性在肝脏中，不同于其他非血红素物质的效力和特异性的肝脏，并在利用机制（S），既不需要生产肝毒性，消耗肝谷胱甘肽，也不敏感放线菌素D。
Hepatic heme oxygenase, an enzyme which converts heme to carbon monoxide and bile pigmentin vitro, is inducible by heme but also by large “toxic” doses of such nonheme substances as hormones, endotoxin, and heavy metal ions. When we gave rats a single hepatotoxic dose of allyl alcohol, ethionine, acetaminophen, furosemide, or endotoxin, hepatic heme oxygenase activity rose modestly (two- to fivefold) after 20 h. In contrast, administration of bromobenzene (5 mmol/kg) induced heme oxygenase in the liver an average of 15-fold after 20 h but was without effect on the enzyme in the kidney or spleen. The change in heme oxygenase was accompanied by a loss in cytochromeP-450 concentration and, in rats labeled with 5-δ-amino[14C]levulinic acid, an increased rate of degradation of hepatic [14C]heme to14CO. Induction of heme oxygenase by bromobenzene was blocked by cycloheximide, an inhibitor of protein synthesis, but not by actinomycin D, an inhibitor of RNA synthesis. This suggests that bromobenzene stimulatesde novoenzyme synthesis at the step of translation. Subtoxic doses of bromobenzene (less than 1 mmol/kg) gave proportionately greater induction of heme oxygenase. Furthermore, induction of the enzyme remained unaffected when bromobenzene hepatotoxicity was blocked by pretreatment of rats with SKF-525A, 3-methylcholanthrene, or cysteine (which supplements liver sulfhydryl content), or when hepatotoxicity was enhanced by pretreatment with phenobarbital or with diethylmaleate (which depletes hepatic glutathione). These data suggest that with induction of heme oxygenase by bromobenzene, neither liver cell necrosis nor alteration in hepatic sulfhydryl metabolism is indispensible. The latter characteristic differs from induction of the enzyme by metal ions in which depletion of sulfhydryl-containing constituents has been thought to be essential. We conclude that bromobenzene is a novel inducer of heme oxygenase activity in the liver, differing from other nonheme substances in potency and specificity for the liver, and in utilizing mechanism(s) which require neither production of hepatotoxicity, depletion of hepatic glutathione, nor sensitivity to actinomycin D.