COMPARATIVE TOXICITY AND ANTIOXIDANT ACTIVITY OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE AND ITS MONOAMINE-OXIDASE B-GENERATED METABOLITES IN ISOLATED HEPATOCYTES AND LIVER-MICROSOMES
COMPARATIVE TOXICITY AND ANTIOXIDANT ACTIVITY OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE AND ITS MONOAMINE-OXIDASE B-GENERATED METABOLITES IN ISOLATED HEPATOCYTES AND LIVER-MICROSOMES
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DOI：
10.1016/0003-9861(87)90289-x
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发表时间：
1987-05-15
影响因子：
3.9
通讯作者：
SMITH, MT
中科院分区：
文献类型：
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作者：
EKSTROM, G;DIMONTE, D;SMITH, MT
MPTP（1-甲基-4-苯基-1，2，3，6-四氢吡啶）被单胺氧化酶B通过MPDP+（1-甲基-4-苯基-2，3-二氢吡啶离子）转化为其推定的毒性代谢产物MPP+（1-甲基-4-苯基吡啶离子）。母体化合物和这两种主要代谢产物均对分离的大鼠肝细胞具有毒性，其中MPDP+毒性最大，MPP+的有效性最低。MPP+在肝细胞中产生了高于对照水平的脂质过氧化作用的轻微增加，而MPTP和MPDP+均显示出抗氧化作用。后两种化合物也保护对化学和非化学诱导的脂质过氧化作用在大鼠肝微粒体。MPDP+在比MPTP低得多的浓度下有效。当使用NADPH诱导微粒体脂质过氧化时，MPDP+的效率也明显更高。因此，脂质过氧化作为氧自由基产生的结果是不太可能参与MPTP的体外毒性和使用链断裂抗氧化剂作为体内保护剂的理由需要更仔细的评估。
MPTP (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is converted by monoamine oxidase B to its putative toxic metabolite MPP+ (1-methyl-4-phenylpyridinium ion) via MPDP+ (1-methyl-4-phenyl-2,3-dihydropyridinium ion). Both the parent compound and these two major metabolites were toxic to isolated rat hepatocytes with MPDP+ being the most toxic and MPP+ the least effective. MPP+ produced a slight increase in lipid peroxidation above control levels in hepatocytes, while both MPTP and MPDP+ showed antioxidant effects. The latter two compounds also protected against chemically and nonchemically induced lipid peroxidation in rat liver microsomes. MPDP+ was effective at much lower concentrations than MPTP. MPDP+ was also markedly more efficient when NADPH was used to induce microsomal lipid peroxidation. Lipid peroxidation as a consequence of oxygen radical generation is therefore unlikely to be involved in MPTP toxicity in vitro and the rationale of using chain-breaking antioxidants as protective agents in vivo needs a more careful evaluation.