Fuller R W, Hemrick-Luecke S K
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Toxicol Lett. 1990 Dec;54(2-3):253-62. doi: 10.1016/0378-4274(90)90192-o.
Tissue concentrations of MPP+ (1-methyl-4-phenylpyridinium) were measured in Charles River CFW mice after administration of high doses of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) or MPP+ given subcutaneously or orally, to investigate the relationships between tissue concentrations and lethality resulting from these compounds. MPTP given subcutaneously led to much higher concentrations of MPP+ in brain and somewhat higher concentrations of MPP+ in peripheral tissues than did MPTP given orally. MPTP caused no lethality at oral doses up to 160 mg/kg whereas subcutaneous MPTP had an LD50 of 54 mg/kg. Deprenyl pretreatment antagonized the lethality of subcutaneous MPTP and reduced MPP+ concentrations in brain and in other tissues after MPTP injection. Deprenyl caused a greater and longer-lasting inhibition of MPTP oxidation than of phenylethylamine oxidation, especially in liver, although both compounds are thought to be oxidized by monoamine oxidase type B. The protective effect of deprenyl against MPTP lethality implicates MPP+ (or possibly some other metabolite) in the lethality after MPTP injection. The reduced lethality of MPTP when given orally and the relative lack of brain levels of MPTP or MPP+ after oral MPTP implicate the brain as a target organ in the lethality of MPTP. Lethality after MPP+ administration almost certainly does not involve the brain, since little or no MPP+ could be measured in brain after oral or subcutaneous dosing of MPP+.
在给Charles River CFW小鼠皮下或口服高剂量的MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）或MPP⁺（1-甲基-4-苯基吡啶鎓）后，测量其组织中MPP⁺的浓度，以研究这些化合物的组织浓度与致死率之间的关系。与口服MPTP相比，皮下注射MPTP导致脑中MPP⁺的浓度高得多，外周组织中MPP⁺的浓度也略高。口服剂量高达160 mg/kg的MPTP不会导致致死，而皮下注射MPTP的半数致死量（LD50）为54 mg/kg。司来吉兰预处理可拮抗皮下注射MPTP的致死性，并降低注射MPTP后脑中及其他组织中MPP⁺的浓度。司来吉兰对MPTP氧化的抑制作用比对苯乙胺氧化的抑制作用更大且持续时间更长，尤其是在肝脏中，尽管这两种化合物都被认为是由B型单胺氧化酶氧化的。司来吉兰对MPTP致死性的保护作用表明MPP⁺（或可能是其他一些代谢物）参与了MPTP注射后的致死过程。口服MPTP时其致死性降低，且口服MPTP后脑中MPTP或MPP⁺的水平相对较低，这表明脑是MPTP致死作用的靶器官。MPP⁺给药后的致死作用几乎肯定不涉及脑，因为口服或皮下注射MPP⁺后脑中几乎检测不到MPP⁺或检测到的MPP⁺很少。
