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首页> 外文期刊>Archives of Toxicology >Phenethyl isocyanate is not the metabolite of phenethyl isothiocyanate responsible for mechanism-based inhibition of cytochrome P450
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Phenethyl isocyanate is not the metabolite of phenethyl isothiocyanate responsible for mechanism-based inhibition of cytochrome P450

机译：异硫氰酸苯乙酯不是异硫氰酸苯乙酯的代谢产物，可基于机理抑制细胞色素P450

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摘要

Phenethyl isothiocyanate is a chemopreventive phytochemical present in cruciferous vegetables where it exists as the glucosinolate gluconasturtiin. It is a mechanism-based inhibitor of both rat and human cytochrome P450 enzymes. The principal objective of the present study was to ascertain whether phenethyl isocyanate, formed by the cytochrome P450-mediated oxidative desulphuration of phenethyl isothiocyanate, is the metabolite responsible for the mechanism-based inhibition. Phenethyl isothiocyanate, following incubation with Aroclor 1254-induced rat liver microsomes in the presence of NADPH, markedly suppressed the CYP1A-mediated O-deethylation of ethoxyresorufin; extent of inhibition was directly related to the pre-incubation time and was antagonised by reduced glutathione. When human liver microsomes were used, the inhibitory effect of phenethyl isothiocyanate, which was once again related to the pre-incubation time, was even more pronounced. When the ability of phenethyl isothiocyanate and phenethyl isocyanate to directly inhibit the O-deethylation of ethoxyresorufin in rat microsomes was compared, the latter compound was only moderately more effective. In human microsomes, both compounds were equipotent. In phenobarbital-induced lung microsomes, phenethyl isothiocyanate was a direct and potent inhibitor of the O-depentylation of pentoxyresorufin; pre-incubation of the isothiocyanate had no impact. Human precision-cut liver slices were more effective than rat slices in metabolising phenethyl isothiocyanate. Pre-treatment of rats, however, with phenobarbitone significantly enhanced the metabolism of isothiocyanate. It may be inferred from the present studies that: (a) phenethyl isocyanate is not the metabolite of phenethyl isothiocyanate responsible for its mechanism-based inhibition, and (b) CYP2B is an important catalyst of the metabolism of phenethyl isothiocyanate.
机译：异硫氰酸苯乙基酯是一种十字花科蔬菜中存在的化学预防性植物化学物质，它以芥子油苷葡萄糖苷二糖苷存在。它是大鼠​​和人类细胞色素P450酶的一种基于机理的抑制剂。本研究的主要目的是确定由细胞色素P450介导的苯乙基异硫氰酸酯的氧化脱硫形成的苯乙基异氰酸酯是否是负责基于机理的抑制作用的代谢物。在NADPH存在下与Aroclor 1254诱导的大鼠肝微粒体温育后，异硫氰酸苯乙酯显着抑制CYP1A介导的乙氧基间苯二酚的O-脱乙基作用。抑制程度与预孵育时间直接相关，并被还原型谷胱甘肽拮抗。当使用人肝微粒体时，异硫氰酸苯乙酯的抑制作用再一次与预孵育时间有关，这种抑制作用甚至更加明显。当比较了异硫氰酸苯乙酯和异氰酸苯乙酯直接抑制大鼠微粒体中乙氧基间苯二酚的O-脱乙基的能力时，后者的化合物仅较有效。在人微粒体中，两种化合物都是等价的。在苯巴比妥诱导的肺微粒体中，异硫氰酸苯乙酯是戊氧基间苯二酚的O-去戊基化的直接有效抑制剂。异硫氰酸酯的预孵育没有影响。精确切割的人肝切片在代谢苯乙基异硫氰酸酯方面比大鼠切片更有效。然而，用苯巴比妥预处理的大鼠可显着增强异硫氰酸酯的代谢。从本研究中可以推断出：（a）异乙基苯乙基异氰酸酯不是基于其机理抑制作用的异乙基苯乙基异硫氰酸酯的代谢产物，并且（b）CYP2B是异乙基苯乙基异硫氰酸酯代谢的重要催化剂。

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