Bogdanffy M S, Taylor M L
Haskell Laboratory for Toxicology and Industrial Medicine, E.I. du Pont de Nemours and Co., Newark, DE 19714.
Drug Metab Dispos. 1993 Nov-Dec;21(6):1107-11.
Vinyl acetate vapor has been shown to produce tumors of the nasal cavity in rats, but not mice, exposed by the inhalation route. Carboxylesterase-mediated hydrolysis of vinyl acetate produces acetic acid and vinyl alcohol, which rearranges to form acetaldehyde, another nasal carcinogen that could be the ultimate carcinogenic metabolite of vinyl acetate. The purpose of this study was to define the kinetics of hydrolysis of vinyl acetate in nasal respiratory and olfactory mucosa of male and female rats and mice. The results showed few differences in kinetic parameters between male and female rats or mice. Differences were observed between mucosae. In respiratory mucosa, Vmax ranged from approximately 22-46 mumol/min/mg protein. In olfactory mucosa, Vmax was significantly higher and ranged from 89 to 165 mumol/min/mg protein. Substrate inhibition was apparent at high substrate concentrations in some cases and for those, a kinetic model that accounted for substrate inhibition fit the data better than a Michaelis-Menten model. The substrate inhibition model yielded Vmax values for olfactory tissues that ranged from 113 to 254 mumol/min/mg protein. The second-order rate constant for binding and catalysis, V/K, ranged from 52 to 79 mumol/min/mg/mM for respiratory tissue and from 270 to 469 mumol/min/mg/mM for olfactory tissue. KM derived from the best-fit models was similar for most tissues and ranged from 0.30 to 1.07 mM. These data demonstrate the high capacity of nasal tissue to metabolize vinyl acetate to acetaldehyde and may explain, in part, vinyl acetate-induced nonneoplastic nasal lesion distribution. However, the data do not account for the species difference in susceptibility to the carcinogenic effects of vinyl acetate.
已证实，通过吸入途径接触醋酸乙烯酯蒸汽的大鼠会产生鼻腔肿瘤，但小鼠不会。醋酸乙烯酯经羧酸酯酶介导水解生成乙酸和乙烯醇，乙烯醇重排形成乙醛，乙醛是另一种鼻腔致癌物，可能是醋酸乙烯酯的最终致癌代谢物。本研究的目的是确定雄性和雌性大鼠及小鼠鼻腔呼吸黏膜和嗅黏膜中醋酸乙烯酯的水解动力学。结果显示，雄性和雌性大鼠或小鼠的动力学参数差异不大。不同黏膜之间存在差异。在呼吸黏膜中，Vmax范围约为22 - 46 μmol/min/mg蛋白质。在嗅黏膜中，Vmax显著更高，范围为89至165 μmol/min/mg蛋白质。在某些情况下，高底物浓度下会出现底物抑制现象，对于这些情况，考虑底物抑制的动力学模型比米氏模型更能拟合数据。底物抑制模型得出嗅组织的Vmax值范围为113至254 μmol/min/mg蛋白质。结合和催化的二级速率常数V/K，呼吸组织为52至79 μmol/min/mg/mM，嗅组织为270至469 μmol/min/mg/mM。从最佳拟合模型得出的KM对大多数组织来说相似，范围为0.30至1.07 mM。这些数据表明鼻腔组织将醋酸乙烯酯代谢为乙醛的能力很强，这可能部分解释了醋酸乙烯酯诱导的非肿瘤性鼻腔病变分布。然而，这些数据无法解释醋酸乙烯酯致癌作用敏感性的种属差异。
