My research activity started with studies on drug metabolism in rat liver microsomes in the early 1960s. The CO-binding pigment (cytochrome P450) had been discovered a few years earlier and was subsequently found to be involved in steroid hydroxylation in adrenal cortex microsomes. Our early studies suggested that it also participated in the oxidative demethylation of drugs catalyzed by liver microsomes, and that prior treatment of the animals with phenobarbital caused increased levels of the hemoprotein in the liver, and similarly enhanced rates of drug metabolism. Subsequent studies of cytochrome P450-mediated metabolism of toxic drugs in freshly isolated rat hepatocytes characterized critical cellular defense systems and identified mechanisms by which accumulating toxic metabolites could damage and kill the cells. These studies revealed that multiple types of cell death could result from the toxic injury, and that it is important to know which type of cell death results from the toxic injury.

中文翻译：

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细胞死亡在毒理学中的作用：细胞死亡如何重要？

我的研究活动始于1960年代初期对大鼠肝微粒体中药物代谢的研究。早在几年前就发现了与CO结合的色素（细胞色素P450），随后发现它与肾上腺皮质微粒体中的甾体羟基化有关。我们的早期研究表明，它也参与了由肝微粒体催化的药物的氧化脱甲基作用，并且先后用苯巴比妥治疗动物会导致肝脏中血红蛋白水平升高，并同样提高了药物代谢率。对新鲜分离的大鼠肝细胞中细胞色素P450介导的有毒药物代谢的后续研究表征了关键的细胞防御系统，并确定了积累有毒代谢产物可能破坏和杀死细胞的机制。