Mueller S O, Stopper H, Dekant W
Department of Toxicology, University of Würzburg, Versbacherstr. 9, 97078 Würzburg, Germany.
Drug Metab Dispos. 1998 Jun;26(6):540-6.
The studies presented here were designed to elucidate the enzymes involved in the biotransformation of naturally occurring 1, 8-dihydroxyanthraquinones and to investigate whether biotransformation of 1,8-dihydroxyanthraquinones may represent a bioactivation pathway. We first studied the metabolism of emodin (1, 3,8-trihydroxy-6-methylanthraquinone), a compound present in pharmaceutical preparations. With rat liver microsomes, the formation of two emodin metabolites, omega-hydroxyemodin and 2-hydroxyemodin, was observed. The rates of formation of omega-hydroxyemodin were not different with microsomes from rats that had been pretreated with inducers for different cytochrome P450 enzymes. Thus, the formation of omega-hydroxyemodin seems to be catalyzed by several cytochrome P450 enzymes at low rates. The formation of 2-hydroxyemodin was increased in liver microsomes from 3-methylcholanthrene-pretreated rats and was inhibited by alpha-naphthoflavone, by an anti-rat cytochrome P450 1A1/2 antibody, and, to a lesser degree, by an anti-rat cytochrome P450 1A1 antibody. These data suggest the involvement of cytochrome P450 1A2 in the formation of this metabolite. However, other cytochrome P450 enzymes also seem to catalyze this reaction. The anthraquinone chrysophanol (1,8-dihydroxy-3-methylanthraquinone) is transformed, in a cytochrome P450-dependent oxidation, to aloe-emodin (1, 8-dihydroxy-3-hydroxymethylanthraquinone) as the major product formed. The mutagenicity of the parent dihydroxyanthraquinones and their metabolites was compared in the in vitro micronucleus test in mouse lymphoma L5178Y cells. 2-Hydroxyemodin induced much higher micronucleus frequencies, compared with emodin. omega-Hydroxyemodin induced lower micronucleus frequencies, compared with emodin. Aloe-emodin induced significantly higher micronucleus frequencies than did chrysophanol. These data indicate that the cytochrome P450-dependent biotransformation of emodin and chrysophanol may represent bioactivation pathways for these compounds.
本文所呈现的研究旨在阐明参与天然存在的1,8 - 二羟基蒽醌生物转化的酶，并探究1,8 - 二羟基蒽醌的生物转化是否可能代表一种生物活化途径。我们首先研究了大黄素（1,3,8 - 三羟基 - 6 - 甲基蒽醌）的代谢，大黄素是药物制剂中的一种化合物。在大鼠肝微粒体中，观察到了两种大黄素代谢产物的形成，即ω - 羟基大黄素和2 - 羟基大黄素。用不同细胞色素P450酶诱导剂预处理的大鼠的微粒体，ω - 羟基大黄素的形成速率并无差异。因此，ω - 羟基大黄素的形成似乎由几种细胞色素P450酶以较低速率催化。在经3 - 甲基胆蒽预处理的大鼠的肝微粒体中，2 - 羟基大黄素的形成增加，并且被α - 萘黄酮、抗大鼠细胞色素P450 1A1/2抗体以及在较小程度上被抗大鼠细胞色素P450 1A1抗体所抑制。这些数据表明细胞色素P450 1A2参与了该代谢产物的形成。然而，其他细胞色素P450酶似乎也催化此反应。蒽醌大黄酚（1,8 - 二羟基 - 3 - 甲基蒽醌）在细胞色素P450依赖性氧化作用下转化为芦荟大黄素（1,8 - 二羟基 - 3 - 羟甲基蒽醌），这是形成的主要产物。在小鼠淋巴瘤L5178Y细胞的体外微核试验中比较了母体二羟基蒽醌及其代谢产物的致突变性。与大黄素相比，2 - 羟基大黄素诱导的微核频率高得多。与大黄素相比，ω - 羟基大黄素诱导的微核频率较低。芦荟大黄素诱导的微核频率显著高于大黄酚。这些数据表明大黄素和大黄酚的细胞色素P450依赖性生物转化可能代表这些化合物的生物活化途径。
