INHIBITION OF CYTOCHROME-P-450 2E1 BY DIALLYL SULFIDE AND ITS METABOLITES
INHIBITION OF CYTOCHROME-P-450 2E1 BY DIALLYL SULFIDE AND ITS METABOLITES
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DOI：
10.1021/tx00024a008
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发表时间：
1991-11-01
影响因子：
4.1
通讯作者：
YANG, CS
中科院分区：
文献类型：
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作者：
BRADY, JF;ISHIZAKI, H;YANG, CS
二烯丙基硫醚是大蒜中的一种主要风味成分，先前在动物模型系统中被证明可以抑制化学诱导的致癌作用和细胞毒性。它通过灭活P-450 2E1和诱导P-450 2B1来调节细胞色素P-450组成。本研究考察了二烯丙基硫醚及其推定代谢物二烯丙基亚砜和二烯丙基砜（DASO2）对P-450 2E1介导的对硝基酚羟化酶活性的抑制作用。在丙酮预处理的雄性Sprague-Dawley大鼠肝微粒体孵育过程中，每种化合物都表现出对硝基酚羟化酶活性的竞争性抑制。用DASO2灭活对硝基酚羟化酶活性的微粒体的预孵育过程是一个时间和nadph依赖且饱和的过程，表现出伪一级动力学，受到交替底物的保护，伴随着微粒体P-450-CO结合谱的丧失，并且不受外源亲核试剂的影响。DASO2的K(i)值为188 mu- m，最大失活率为0.32 min-1。DASO2对乙氧基间苯二酚脱烷基酶、戊氧基间苯二酚脱烷基酶或苯丙胺脱甲基酶活性失活无效。重组体系中纯化的P-450 2E1以时间和nadph依赖的方式被DASO2灭活。在体内和体外观察了二烯丙基硫醚转化为亚砜和砜的代谢过程。结果表明，二烯丙基硫醚通过竞争性抑制机制抑制P-450 2E1底物的代谢，并通过DASO2的自杀抑制作用使P-450 2E1失活。
Diallyl sulfide, a major flavor ingredient from garlic, was previously shown to inhibit chemically induced carcinogenesis and cytotoxicity in animal model systems. It modulated cytochrome P-450 compositions by inactivating P-450 2E1 and inducing P-450 2B1. The present studies examined the inhibition of P-450 2E1 mediated p-nitrophenol hydroxylase activity by diallyl sulfide and its putative metabolites diallyl sulfoxide and diallyl sulfone (DASO2). Each compound displayed competitive inhibition of p-nitrophenol hydroxylase activity in incubations using liver microsomes from acetone-pretreated male Sprague-Dawley rats. Preincubation of the microsomes with DASO2 inactivated p-nitrophenol hydroxylase activity in a process that was time- and NADPH-dependent and saturable, exhibited pseudo-first-order kinetics, was protected by alternate substrate, was accompanied by a loss of microsomal P-450-CO binding spectrum, and was unaffected by exogenous nucleophile. The K(i) value for DASO2 was 188-mu-M and the maximal rate of inactivation was 0.32 min-1. DASO2 was ineffective in the inactivation of ethoxyresorufin dealkylase, pentoxyresorufin dealkylase, or benzphetamine demethylase activity. Purified P-450 2E1 in a reconstituted system was inactivated in a time- and NADPH-dependent manner by DASO2. The metabolic conversion of diallyl sulfide to the sulfoxide and sulfone was observed in vivo and in vitro. The results suggest that diallyl sulfide inhibits the metabolism of P-450 2E1 substrates by competitive inhibition mechanisms and by inactivating P-450 2E1 via a suicide-inhibitory action of DASO2.