Lincoln B C, Healey J F, Bonkovsky H L
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322.
Biochem J. 1988 Feb 15;250(1):189-96. doi: 10.1042/bj2500189.
We studied drug- and metal-mediated increases in activity of haem oxygenase, the rate-controlling enzyme for haem breakdown, in chick-embryo hepatocytes in ovo and in primary culture. Phenobarbitone and phenobarbitone-like drugs (glutethimide, mephenytoin), which are known to increase concentrations of an isoform of cytochrome P-450 in chick-embryo hepatocytes, were found to increase activities of haem oxygenase as well. In contrast, 20-methylcholanthrene, which increases the concentration of a different isoform of cytochrome P-450, had no effect on activity of haem oxygenase. Inhibitors of haem synthesis, 4,6-dioxoheptanoic acid or desferrioxamine, prevented drug-mediated induction of both cytochrome P-450 and haem oxygenase in embryo hepatocytes in ovo or in culture. Addition of haem restored induction of both enzymes. These results are interpreted to indicate that phenobarbitone and its congeners induce haem oxygenase by increasing hepatic haem formation. In contrast, increases in haem oxygenase activity by metals such as cobalt, cadmium and iron were not dependent on increased haem synthesis and were not inhibited by 4,6-dioxoheptanoic acid. We conclude that (1) induction of hepatic haem oxygenase activity by phenobarbitone-type drugs is due to increased haem formation, and (2) induction of haem oxygenase by drugs and metals occurs by different mechanisms.
我们研究了药物和金属介导的血红素加氧酶（血红素分解的限速酶）活性增加的情况，研究对象是鸡胚肝细胞，包括在胚胎内和原代培养中的肝细胞。已知苯巴比妥和苯巴比妥类药物（格鲁米特、美芬妥因）可增加鸡胚肝细胞中一种细胞色素P - 450同工酶的浓度，结果发现它们也能增加血红素加氧酶的活性。相比之下，能增加另一种不同细胞色素P - 450同工酶浓度的20 - 甲基胆蒽，对血红素加氧酶的活性没有影响。血红素合成抑制剂4,6 - 二氧庚酸或去铁胺，可阻止药物介导的胚胎肝细胞在胚胎内或培养时细胞色素P - 450和血红素加氧酶两者的诱导。添加血红素可恢复这两种酶的诱导。这些结果被解释为表明苯巴比妥及其同系物通过增加肝脏血红素的形成来诱导血红素加氧酶。相比之下，钴、镉和铁等金属引起的血红素加氧酶活性增加并不依赖于血红素合成的增加，且不受4,6 - 二氧庚酸的抑制。我们得出结论：（1）苯巴比妥类药物诱导肝脏血红素加氧酶活性是由于血红素形成增加；（2）药物和金属诱导血红素加氧酶是通过不同机制发生的。
