Trela B A, Bogdanffy M S
Haskell Laboratory for Toxicology and Industrial Medicine, E. I. du Pont de Nemours & Company, Inc., Newark, Delaware 19714.
Toxicol Appl Pharmacol. 1991 Feb;107(2):285-301. doi: 10.1016/0041-008x(91)90209-w.
Dibasic esters (DBE) are a solvent mixture of dimethyl adipate (DMA), dimethyl glutarate (DMG), and dimethyl succinate (DMS) used in the paint and coating industry. Subchronic inhalation toxicity studies have demonstrated that DBE induce a mild degeneration of the olfactory, but not the respiratory, epithelium of the rat nasal cavity. Carboxylesterase-mediated hydrolysis of the individual dibasic esters is more efficient in olfactory than in respiratory mucosal homogenates. In the present study, an in vitro system of cultured rat nasal explants was utilized to determine if DBE toxicity is dependent on a metabolic activation by nonspecific carboxylesterase. Explants from both the olfactory and the respiratory regions of the female rat nasal cavity were incubated for 2 hr in Williams' medium E containing 10-100 mM DMA, DMG, or DMS. DBE caused a dose-related increase in nasal explant acid phosphatase release, a biochemical index of cytotoxicity. HPLC analysis demonstrated parallel increases in the carboxylesterase-mediated formation of monomethyl ester metabolites. Diacid metabolite production in the nasal explant system was not entirely concentration-dependent. Metabolite concentrations and acid phosphatase release were generally greater in olfactory than respiratory tissues. DBE-induced cytotoxicity and acid metabolite production were markedly attenuated in nasal tissue excised from rats which were pretreated with bis(p-nitrophenyl)phosphate, a carboxylesterase inhibitor. This study presents a viable in vitro method for assessing organic ester cytotoxicity in the rat nasal cavity. It was shown that DBE are weak nasal toxicants under the conditions of this system. It was further demonstrated that DBE toxicity is dependent on a carboxylesterase-mediated activation. A similar mechanism was proposed for the nasal toxicity induced by other organic esters following inhalation exposure.
二元酯（DBE）是一种己二酸二甲酯（DMA）、戊二酸二甲酯（DMG）和琥珀酸二甲酯（DMS）的溶剂混合物，用于油漆和涂料行业。亚慢性吸入毒性研究表明，DBE会导致大鼠鼻腔嗅觉上皮而非呼吸上皮出现轻度退化。在嗅觉黏膜匀浆中，羧酸酯酶介导的各二元酯水解比在呼吸黏膜匀浆中更有效。在本研究中，利用培养的大鼠鼻外植体体外系统来确定DBE毒性是否依赖于非特异性羧酸酯酶的代谢活化。将雌性大鼠鼻腔嗅觉和呼吸区域的外植体在含有10 - 100 mM DMA、DMG或DMS的威廉姆斯E培养基中孵育2小时。DBE导致鼻外植体酸性磷酸酶释放呈剂量相关增加，这是细胞毒性的生化指标。高效液相色谱分析表明，羧酸酯酶介导的单甲酯代谢产物形成呈平行增加。鼻外植体系统中的二酸代谢产物生成并非完全依赖浓度。嗅觉组织中的代谢产物浓度和酸性磷酸酶释放通常高于呼吸组织。在用羧酸酯酶抑制剂双（对硝基苯基）磷酸酯预处理的大鼠切除的鼻组织中，DBE诱导的细胞毒性和酸性代谢产物生成明显减弱。本研究提出了一种可行的体外方法来评估大鼠鼻腔中有机酯的细胞毒性。结果表明，在该系统条件下，DBE是弱鼻毒性物质。进一步证明，DBE毒性依赖于羧酸酯酶介导的活化。对于吸入暴露后其他有机酯诱导的鼻毒性，也提出了类似的机制。
