Prescott-Mathews J S, Poet T S, Borghoff S J
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Toxicol Appl Pharmacol. 1999 May 15;157(1):60-7. doi: 10.1006/taap.1999.8661.
Methyl tert-butyl ether (MTBE), a fuel additive blended into unleaded gasoline, decreases emissions of selected air pollutants. Exposure to MTBE causes a low incidence of renal tumors in male, but not female, F-344 rats. A number of chemicals that cause male rat-specific renal tumors also cause a syndrome unique to male rats referred to as alpha2u-globulin (alpha2u) nephropathy (alpha2u-N). Previous investigations have demonstrated that MTBE exposure induces a mild accumulation of alpha2u in male F-344 rats. The objective of the present study was to determine if MTBE, or a metabolite of MTBE, interacts with alpha2u in male rats administered MTBE orally. Eleven-week-old male and female F-344 rats were administered 750 mg [14C]MTBE/kg body wt or an equivalent volume of 10% emulphor orally for 4 consecutive days. Although [14C]MTBE-treated male rats exhibited a statistically significant increase in renal alpha2u concentration, the total radioactivity recovered was similar in kidney samples from [14C]MTBE-treated male and female rats. Further analysis of kidney cytosol prepared from [14C]MTBE-treated rats revealed that a slightly greater percentage of radioactivity coeluted on a G-25 gel filtration column with the total protein fraction from male rats than from female rats. Gel filtration (Sephadex G-75 column) and anion exchange chromatography, however, did not demonstrate any coelution of MTBE-derived radioactivity with the low-molecular-weight protein fraction or alpha2u fraction, respectively, in kidney cytosol prepared from [14C]MTBE-treated male or female rats. Further experimentation using a sealed vial equilibration system demonstrated that d-limonene oxide, a chemical with a high affinity for alpha2u, displaced MTBE in male, but not female, rat kidney samples following administration of MTBE. These findings provide indirect evidence that MTBE interacts with a male-specific protein such as alpha2u in male F-344 rats. Since the pathogenesis of alpha2u-N is dependent on the formation of a reversibly bound chemical-alpha2u complex, demonstration of an in vivo interaction of MTBE or one of its metabolites with alpha2u supports the alpha2u mechanism as a cause of MTBE-induced protein droplet nephropathy in male rats.
甲基叔丁基醚（MTBE）是一种添加到无铅汽油中的燃料添加剂，可减少特定空气污染物的排放。雄性F-344大鼠接触MTBE后肾肿瘤发病率较低，但雌性大鼠未出现这种情况。许多导致雄性大鼠特异性肾肿瘤的化学物质还会引发一种雄性大鼠特有的综合征，称为α2u球蛋白（α2u）肾病（α2u-N）。先前的研究表明，接触MTBE会导致雄性F-344大鼠体内α2u轻度蓄积。本研究的目的是确定MTBE或其代谢产物是否会与经口给予MTBE的雄性大鼠体内的α2u发生相互作用。给11周龄的雄性和雌性F-344大鼠连续4天经口给予750 mg [14C]MTBE/kg体重或等量的10%乳化剂。虽然经[14C]MTBE处理的雄性大鼠肾内α2u浓度有统计学意义的显著升高，但在经[14C]MTBE处理的雄性和雌性大鼠的肾脏样本中，回收的总放射性相似。对经[14C]MTBE处理的大鼠制备的肾细胞溶质进行进一步分析发现，与雌性大鼠相比，在G-25凝胶过滤柱上与雄性大鼠总蛋白部分共洗脱的放射性百分比略高。然而，凝胶过滤（Sephadex G-75柱）和阴离子交换色谱分析均未显示在经[14C]MTBE处理的雄性或雌性大鼠制备的肾细胞溶质中，MTBE衍生的放射性分别与低分子量蛋白部分或α2u部分有共洗脱现象。使用密封小瓶平衡系统进行的进一步实验表明，对α2u具有高亲和力的化学物质氧化d-苎烯在给予MTBE后，能置换雄性大鼠而非雌性大鼠肾脏样本中的MTBE。这些发现提供了间接证据，表明MTBE与雄性F-344大鼠体内的α2u等雄性特异性蛋白发生相互作用。由于α2u-N的发病机制依赖于可逆结合的化学物质-α2u复合物的形成，MTBE或其代谢产物之一与α2u在体内发生相互作用的证明支持了α2u机制是MTBE诱导雄性大鼠蛋白滴状肾病的原因。
