代谢
大鼠鼻粘膜组织对二元酸酯的新陈代谢进行了体外研究。从Crl:CDBR-rat的嗅区和呼吸区（包括鼻甲和上颌甲）取得的嗅组织和呼吸组织的匀浆与丁二酸二甲酯、戊二酸二甲酯或己二酸二甲酯一起培养。计算了在饱和底物浓度下的反应速度（Vmax）、结合和催化的二级速率常数（V/K）、米氏常数（Km）以及产生半最大抑制反应速度所需的二元酸酯浓度（Ksi）。二元酸酯被嗅组织和呼吸组织的匀浆水解为单甲基酯。没有检测到二酸代谢物。水解速率在嗅组织中总是比呼吸组织中快。雄性大鼠嗅组织的Vmax是呼吸组织的5到9倍。在雌性大鼠中，嗅组织的Vmax是呼吸粘膜的6到13倍。雄性和雌性嗅组织的V/K分别是相应呼吸组织的4到11倍和6到10倍。当戊二酸二甲酯作为底物时，雄性和雌性嗅组织的V/K相似。对于丁二酸二甲酯和己二酸二甲酯，雌性嗅组织的V/K值分别是雄性组织的0.5倍和2倍。当己二酸二甲酯作为底物时，嗅组织的Km值最大，其次是丁二酸二甲酯和戊二酸二甲酯。Ki值范围从24到46.5毫摩尔。雌性大鼠预先用1%的双对硝基苯磷酸处理，这是一种针对羧酸酯酶的特异性抑制剂。双对硝基苯磷酸使嗅组织中丁二酸二甲酯、戊二酸二甲酯和己二酸二甲酯的水解速率分别降低了79.8%、81%和72%。相应的，呼吸组织中的水解速率降低了87%、73%和95%。作者得出结论，吸入酯类在大鼠鼻腔内引起的损伤可能是由有毒的酸性代谢物引起的。
The metabolism of dibasic esters by rat nasal mucosal tissues was studied in-vitro. Homogenates of olfactory tissue from the ethmoturbinates and respiratory tissue from the nasoturbinates and maxilloturbinates of Crl:CDBR-rats were incubated with dimethyl succinate, dimethyl glutarate, or dimethyl adipate. Values of the reaction velocity at saturating substrate concentration (Vmax), the second order rate constant for binding and catalysis (V/K), the Michaelis constant (Km), and the dibasic ester concentration required to produce half maximal inhibition of the reaction rate (Ksi) were computed. The dibasic esters were hydrolyzed to their monomethyl esters by both the olfactory and respiratory mucosal homogenates. No diacid metabolites were detected. The rates of hydrolysis were always greater in the olfactory than in the respiratory homogenates. Vmaxs in olfactory tissue from male rats were 5 to 9 times higher than in respiratory tissue. In female rats, Vmaxs in the olfactory homogenates were 6 to 13 times those of the respiratory mucosa. V/Ks in male and female olfactory tissue were 4 to 11 and 6 to 10 times those in the corresponding respiratory tissue, respectively. When dimethyl glutarate was used as the substrate, V/Ks were similar for male and female olfactory tissue. In the case of dimethyl succinate and dimethyl adipate, V/K values for female olfactory tissue were 0.5 and 2 times those of the male tissues, respectively. The largest Km values in the olfactory tissues occurred when dimethyl adipate was used as the substrate, followed by dimethyl adipate and dimethyl glutarate in that order. The Ki values ranged from 24 to 46.5 millimolar. Female rats were pretreated with 1% bis-p-nitrophenyl phosphate, a carboxylesterase specific inhibitor. Bis-p-nitrophenyl phosphate decreased the rates of hydrolysis of dimethyl adipate, dimethyl glutarate, and dimethyl succinate in olfactory tissue by 79.8, 81, and 72%, respectively. The corresponding rates of hydrolysis in respiratory tissue were reduced by 87, 73, and 95%. The authors conclude that lesions induced in the nasal cavity of rodents by inhaled esters may be due to toxic acid metabolites.
来源:Hazardous Substances Data Bank (HSDB)
