Maples K R, Jordan S J, Mason R P
Laboratory of Molecular Biophysics, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Drug Metab Dispos. 1988 Nov-Dec;16(6):799-803.
We have employed the ESR spin trapping technique in vivo to detect the formation of the 5,5-dimethyl-1-pyrroline N-oxide (DMPO)/hemoglobin thiyl free radical adduct in the blood of rats following administration of hydrazine-based drugs. The drugs examined were isoniazid, iproniazid, phenelzine, and hydralazine. In addition, phenylhydrazine and acetylhydrazine were also studied in a like manner. Of the four drugs, only phenelzine and iproniazid were able to induce the formation of the DMPO/hemoglobin thiyl free radical adduct in vivo, whereas only phenelzine and hydralazine were able to form this adduct in vitro. We were able to decrease the in vivo iproniazid-induced adduct formation by pretreating the rats with bis-para-nitrophenylphosphate, an arylamidase inhibitor. Our results support the idea that iproniazid is hydrolyzed in the liver to a more reactive metabolite, most likely isopropylhydrazine, which is subsequently released into the blood stream. In addition to the drug studies, experiments were performed to provide additional evidence that the radical adduct we detected was indeed of a hemoglobin thiyl free radical. Studies employing alpha-phenyl-N-t-butylnitrone (PBN) as the spin trap in place of DMPO also showed the formation of the PBN/hemoglobin thiyl free radical adduct.
我们采用电子自旋共振（ESR）自旋捕获技术在体内检测肼基药物给药后大鼠血液中5,5-二甲基-1-吡咯啉N-氧化物（DMPO）/血红蛋白硫自由基加合物的形成。所检测的药物有异烟肼、异卡波肼、苯乙肼和肼屈嗪。此外，苯肼和乙酰肼也以同样的方式进行了研究。在这四种药物中，只有苯乙肼和异卡波肼能够在体内诱导DMPO/血红蛋白硫自由基加合物的形成，而只有苯乙肼和肼屈嗪能够在体外形成这种加合物。我们通过用芳基酰胺酶抑制剂对硝基苯基磷酸双酯预处理大鼠，能够减少体内异卡波肼诱导的加合物形成。我们的结果支持这样一种观点，即异卡波肼在肝脏中水解为一种更具反应性的代谢物，很可能是异丙肼，随后释放到血流中。除了药物研究外，还进行了实验以提供额外的证据，证明我们检测到的自由基加合物确实是血红蛋白硫自由基。使用α-苯基-N-叔丁基硝酮（PBN）代替DMPO作为自旋捕获剂的研究也表明形成了PBN/血红蛋白硫自由基加合物。
