Weller P E, Narasimhan N, Buben J A, Hanzlik R P
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045-2500.
Drug Metab Dispos. 1988 Mar-Apr;16(2):232-7.
A series of ortho-substituted bromobenzene derivatives with widely differing hepatotoxicities were investigated for their tendency to undergo oxidative metabolism and protein covalent binding in the presence of rat liver microsomes in vitro. Compounds studied included o-bromobenzonitrile, o-dibromobenzene, bromobenzene, o-bromoanisole, and o-bromotoluene (names in order of decreasing hepatotoxicity and increasing rate of in vitro metabolism). No correlation was found between net covalent binding and toxicity. However, a good rank order correlation was observed between toxicity and the relative binding index of each compounds, defined as (picomoles covalently bound/nmol metabolized), with values ranging from a low of 7 with o-bromotoluene to a high of 365 with o-bromobenzonitrile, Extensive side chain metabolism was observed with o-bromotoluene (92-95%) and o-bromoanisole (26-42%), which accounts for their high rate of total metabolism and low relative binding index. The extent of tritium loss, relative to C-14, was assessed for each compound as an index of the "average oxidation state" of those metabolites, presumably epoxides and/or quinones, which covalently bound to protein. Tritium retention ranged from a high of 84% with o-bromobenzonitrile to a low of 21% with o-bromoanisole, and generally paralleled toxicity. These results show that introduction of ortho-substituents onto bromobenzene leads to qualitative and quantitative changes in overall oxidative metabolism, as well as important qualitative changes in the nature of reactive metabolites formed. Nevertheless, the relative binding index computed for each compound appears to reconcile these changes to a large degree, giving an in vitro index which correlates well with toxicity.
研究了一系列具有广泛不同肝毒性的邻位取代溴苯衍生物在体外大鼠肝微粒体存在下进行氧化代谢和蛋白质共价结合的倾向。所研究的化合物包括邻溴苯腈、邻二溴苯、溴苯、邻溴苯甲醚和邻溴甲苯（按肝毒性降低和体外代谢速率增加的顺序排列）。未发现净共价结合与毒性之间存在相关性。然而，观察到毒性与每种化合物的相对结合指数之间存在良好的等级顺序相关性，相对结合指数定义为（共价结合的皮摩尔数/代谢的纳摩尔数），其值范围从邻溴甲苯的低至7到邻溴苯腈的高至365。观察到邻溴甲苯（92 - 95%）和邻溴苯甲醚（26 - 42%）有广泛的侧链代谢，这解释了它们的高总代谢率和低相对结合指数。评估了每种化合物相对于碳 - 14的氚损失程度，作为与蛋白质共价结合的那些代谢物（可能是环氧化物和/或醌）的“平均氧化态”的指标。氚保留率范围从邻溴苯腈的高至84%到邻溴苯甲醚的低至21%，并且通常与毒性平行。这些结果表明，在溴苯上引入邻位取代基会导致整体氧化代谢在定性和定量上发生变化，以及所形成的反应性代谢物的性质发生重要的定性变化。然而，为每种化合物计算的相对结合指数似乎在很大程度上协调了这些变化，给出了一个与毒性相关性良好的体外指标。
