Studies on the conversion of haloperidol and its tetrahydropyridine dehydration product to potentially neurotoxic pyridinium metabolites by human liver microsomes.
Studies on the conversion of haloperidol and its tetrahydropyridine dehydration product to potentially neurotoxic pyridinium metabolites by human liver microsomes.
复制标题
人肝微粒体将氟哌啶醇及其四氢吡啶脱水产物转化为潜在神经毒性吡啶代谢物的研究。
DOI：
10.1021/tx960001y
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
CastagnolJr,N
中科院分区：
文献类型：
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作者：
Usuki,E;Pearce,R;Parkinson,A;CastagnolJr,N
精神安定药氟哌啶醇（HP）及其四氢吡啶脱水产物HPTP在人类和啮齿类动物中生物转化为潜在神经毒性的HP吡啶鎓物质HPP+和还原型HP吡啶鎓物质RHPP+。本文报告的研究旨在鉴定催化这些转化的人细胞色素P450的特定形式。15份人肝微粒体制备物均催化HP和HPTP氧化为HPP+，HPTP氧化为RHPP+。HPP+和RHPP+形成的forkcat/KMaverage值分别为6.71和1.24 min-1 mM-1。HP和HPTP转化为HPP+的速率与睾酮6β-羟化酶活性（P450 3A活性的标志物）密切相关。从共表达人P450 3A 4和细胞色素P450还原酶的人淋巴母细胞系制备的微粒体也催化HP和HPTP形成HPP+。三乙酰竹桃霉素和酮康唑，有效的P450 3A抑制剂，和抗P450 3A的抗体是HPP+形成的有效抑制剂。我们的结论是，HP和HPTP的潜在的神经毒性吡啶代谢产物HPP+的转换被P450 3A 4在人肝微粒体中选择性催化。
The neuroleptic agent haloperidol (HP) and its tetrahydropyridine dehydration product HPTP are biotransformed to the potentially neurotoxic HP pyridinium species HPP+and the reduced HP pyridinium species RHPP+in humans and rodents. The studies reported here were designed to identify the specific form(s) of human cytochrome P450 that catalyze(s) these transformations. Fifteen human liver microsomal preparations all catalyzed the oxidation of HP and HPTP to HPP+and HPTP to RHPP+. Values forkcat/KMaveraged 6.71 and 1.24 min-1mM-1for HPP+and RHPP+formation, respectively. The rates of conversion of HP and HPTP to HPP+correlated well with testosterone 6β-hydroxylase activity, a marker of P450 3A activity. Microsomes prepared from a human lymphoblastoid cell line co-expressing human P450 3A4 and cytochrome P450 reductase also catalyzed the formation of HPP+from HP and HPTP. Troleandomycin and ketoconazole, potent P450 3A inhibitors, and antibodies against P450 3A were effective inhibitors of HPP+formation. We conclude that the conversions of HP and HPTP to the potentially neurotoxic pyridinium metabolite HPP+are catalyzed selectively by P450 3A4 in human liver microsomes.