Mechanism of metabolic activation of xenobiotics in brain

氟哌啶醇是一种临床上有用的抗精神病药物，但它有严重的锥体外系副作用。氟哌啶醇的活性代谢产物HPP^+可能参与慢性HP治疗药物诱导的帕金森病的发生。HPP^+在肝脏中由P-450 CYP 3A 4形成。在给予HP后，大鼠脑中发现的HPP^+可能在外周形成，然后通过血脑屏障转运。然而，在过氧化物存在的情况下，脑中的HPP^+也是由非P450血红素蛋白形成的。此外，HPP^+不是由非血红素金属离子产生的，而是由金属卟啉与过氧化物结合产生的。随着大鼠年龄的增长，大鼠脑中脂质过氧化物水平的增加导致大鼠脑匀浆中HPP^+的产生增加。提示HP在人脑中形成HPP+可能随年龄增长而增加，可能是老年人帕金森病的易感因素。

Haloperidol is a clinically useful antipsychotic drug, but it has severe extrapyramidal side-effects. HPP^+, the active metabolite of haloperidol, may be involved in the development of drug-induced parkinsonism with chronic HP therapy. HPP^+ was formed by P-450 CYP3A4 in liver. HPP^+ found in rat brain following administration of HP may be formed peripherally and then be transported through the blood-brain barrier. However, HPP^+ in brain was also found to be formed by non-P450 hemoproteins in the presence of the peroxides. Further, HPP^+ was producted not by the nonheme metal ions but by metalloporphyrine in combination with the peroxides. Increase of lipid peroxide levels in rat brain with years of rat resulted in increasing generation of HPP^+ in rat brain homogenates. These findings suggest that formation of HPP+ from HP in human brain may increase with increasing age and it may be easy to cause Parkinson's disease in old age.