Inhibition of metabolism-mediated cytotoxicity by 1,1-disubstituted hydrazines in mouse mastocytoma (line P815) cells.
Inhibition of metabolism-mediated cytotoxicity by 1,1-disubstituted hydrazines in mouse mastocytoma (line P815) cells.
复制标题
1,1-二取代肼在小鼠肥大细胞瘤（P815 系）细胞中抑制代谢介导的细胞毒性。
DOI：
10.1016/0006-2952(82)90264-7
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发表时间：
1982
影响因子：
5.8
通讯作者：
Prough,RA
中科院分区：
文献类型：
--
作者：
Wiebkin,P;Sieg,MS;Nelson,RE;Hines,RN;Prough,RA
Cyclophosphamide (CPA), a compound requiring metabolic activation to form toxic metabolites, has been used as a model compound to validate the use of a hepatocyte/mouse mastocytoma (line P815) cell culture system capable of measuring metabolism-mediated cytotoxicityin vitro. A number of hydrazines were tested in this system and were found to be relatively non-toxic. However, an attempt has been made to correlate complex formation between hydrazine metabolites and cytochrome P-450 in rat hepatocytes and the inhibition of the metabolism-mediated cytotoxicity of CPA.N-Aminopiperidine (NAP) was the most potent hydrazine tested in this system, since it significantly reduced the metabolism-mediated toxicity of CPA. The concentration dependency of this phenomenon permitted the calculation of the amount of NAP that reduced CPA cytotoxicity by 50%. This value (approximately 1 mM) correlated well with the apparent Michaelis constant (1.2 mM) for the formation of the inhibitory metabolite complex with cytochrome P-450 in microsomal suspensions. There was good correlation between the abilities of a number of 1,1-disubstituted hydrazines to reduce the metabolism-mediated toxicity of CPA and the extent to which they form the inhibitory metabolite complex in microsomes. 1,2-Dimethylhydrazine did not form an observable inhibitory complex in microsomal suspensions and only slightly reduced the metabolism-mediated toxicity of CPA in the mouse mastocytoma cell culture system. However, some other hydrazine derivatives were shown to alter significantly cytochrome P-450 function in isolated hepatocytes. Thisin vitrosystem may be of use in the evaluation of the biological effects of xenobiotics, particularly those requiring metabolic activation by cytochrome P-450.
