Chen G M, Bray T M, Janzen E G, McCay P B
Department of Nutritional Sciences, University of Guelph, Ontario, Canada.
Free Radic Res Commun. 1991;14(1):9-16. doi: 10.3109/10715769109088936.
It has been previously demonstrated that alpha-phenyl-N-tert-butyl-nitrone (PBN), one of the most widely used free radical trapping agents, is rapidly absorbed, evenly distributed among a wide range of tissues, and metabolized to form one metabolite. The objective of this study was to determine if the distribution and metabolism of PBN can be affected by inducers or inhibitors of the microsomal mixed function oxidase (MFO) system. Rats were pretreated with MFO inducers (phenobarbital and 3-methylcholanthrene) or MFO inhibitors (metyrapone and piperonyl butoxide) before 14C-PBN was injected (i.p.) The concentrations of 14C-PBN and its metabolite were measured in plasma, urine, liver, lung and kidney 2 hours after injection. The results indicated that when MFO was induced, the concentration of 14C-PBN metabolite was significantly reduced in all tissues measured. The maximum concentration of PBN parent compound in the tissues where MFO was induced was 50% of that found in saline controls. Manipulation of tissue MFO levels with inducers and inhibitors altered the ratio of 14C-PBN parent compound to the PBN-metabolite. When 14C-PBN was incubated with rat liver microsomes at 37 degrees C in the presence of NADPH, the rate of metabolism was 1,752 dpm of 14C-PBN-metabolite formed/nmole P-450/min. Inactivation of MFO by heat (80 degrees C for 1 min) or deletion of NADPH diminished the formation of PBN metabolite in vitro. It is concluded that the MFO system may be responsible for the metabolism of PBN. Tissue concentrations of PBN can be affected by drugs or toxins which are inducers or inhibitors of MFO.
先前已经证明，α-苯基-N-叔丁基硝酮（PBN）是使用最广泛的自由基捕获剂之一，它能被迅速吸收，均匀分布于多种组织中，并代谢形成一种代谢产物。本研究的目的是确定PBN的分布和代谢是否会受到微粒体混合功能氧化酶（MFO）系统的诱导剂或抑制剂的影响。在注射14C-PBN（腹腔注射）之前，用MFO诱导剂（苯巴比妥和3-甲基胆蒽）或MFO抑制剂（甲吡酮和胡椒基丁醚）对大鼠进行预处理。注射后2小时，测定血浆、尿液、肝脏、肺和肾脏中14C-PBN及其代谢产物的浓度。结果表明，当MFO被诱导时，在所有测定的组织中，14C-PBN代谢产物的浓度显著降低。在MFO被诱导的组织中，PBN母体化合物的最大浓度是生理盐水对照组中的50%。用诱导剂和抑制剂操纵组织MFO水平会改变14C-PBN母体化合物与PBN代谢产物的比例。当14C-PBN在37℃下于NADPH存在的情况下与大鼠肝脏微粒体一起孵育时，代谢速率为形成的14C-PBN代谢产物1752 dpm/纳摩尔P-450/分钟。通过加热（在80℃下加热1分钟）或去除NADPH使MFO失活会减少体外PBN代谢产物的形成。得出的结论是，MFO系统可能负责PBN的代谢。PBN的组织浓度可能会受到作为MFO诱导剂或抑制剂的药物或毒素的影响。
