Bentley P, Bieri F, Kuster H, Muakkassah-Kelly S, Sagelsdorff P, Stäubli W, Waechter F
Central Toxicology Unit, Ciba-Geigy Ltd, Basel, Switzerland.
Carcinogenesis. 1989 Feb;10(2):321-7. doi: 10.1093/carcin/10.2.321.
Synergistic interactions have been reported in the carcinogenicity of two epoxy resin components to mouse skin. A mixture of bisphenol A diglycidylether and bis epoxycyclopentylether was highly carcinogenic, despite the fact that neither compound gave positive results when applied individually. To elucidate the mechanism of this synergistic interaction we have investigated the effects of bis epoxycyclopentylether upon the hydrolysis and DNA-binding of bisphenol A diglycidylether. This glycidylether was rapidly hydrolysed by microsomal and cytosolic fractions of mouse liver and skin. In three different mouse strains the specific epoxide hydrolase activities were 28.3-48.5; 33.0-38.8; 7.9-10.2 and 0.85-0.98 nmol/mg protein/min for liver microsomal and cytosolic and skin microsomal and cytosolic fractions respectively. This is the first demonstration of an epoxide hydrolase activity in skin cytosolic fractions. Bis epoxycyclopentylether inhibited the microsomal activities. This inhibition appeared to be slightly more effective with microsomal fractions from liver. The effect of this inhibition upon the binding of bisphenol A diglycidylether to mouse skin DNA was investigated using bisphenol A diglycidylether radiolabelled at two different positions. When high doses of bisphenol A diglycidylether were applied to the mouse skin one major DNA adduct was observed which was identified as a glycidaldehyde adduct. This adduct was not detectable at the lowest bisphenol A diglycidylether dose tested, unless bis epoxycyclopentylether was applied simultaneously. These findings suggest that glycidaldehyde may be formed from bisphenol A diglycidylether. At low doses, however, the epoxide groups are hydrolysed before glycidaldehyde can be formed, unless the epoxide hydrolase is inhibited. Such inhibition and the associated increased production of glycidaldehyde may account for the potentiation of the carcinogenic response in the epoxide mixture.
据报道，两种环氧树脂成分对小鼠皮肤的致癌性存在协同相互作用。双酚A二缩水甘油醚和双环氧环戊醚的混合物具有高度致癌性，尽管单独使用这两种化合物时均未得到阳性结果。为了阐明这种协同相互作用的机制，我们研究了双环氧环戊醚对双酚A二缩水甘油醚水解和与DNA结合的影响。这种缩水甘油醚可被小鼠肝脏和皮肤的微粒体及胞质部分迅速水解。在三种不同的小鼠品系中，肝脏微粒体和胞质部分以及皮肤微粒体和胞质部分的特异性环氧化物水解酶活性分别为28.3 - 48.5；33.0 - 38.8；7.9 - 10.2和0.85 - 0.98 nmol/mg蛋白质/分钟。这是首次证明皮肤胞质部分存在环氧化物水解酶活性。双环氧环戊醚抑制微粒体活性。这种抑制对肝脏微粒体部分似乎略为有效。使用在两个不同位置进行放射性标记的双酚A二缩水甘油醚，研究了这种抑制对双酚A二缩水甘油醚与小鼠皮肤DNA结合的影响。当向小鼠皮肤施用高剂量的双酚A二缩水甘油醚时，观察到一种主要的DNA加合物，其被鉴定为缩水甘油醛加合物。在测试的最低双酚A二缩水甘油醚剂量下，除非同时施用双环氧环戊醚，否则无法检测到这种加合物。这些发现表明，缩水甘油醛可能由双酚A二缩水甘油醚形成。然而，在低剂量下，除非环氧化物水解酶被抑制，否则环氧基团在缩水甘油醛形成之前就会被水解。这种抑制以及相关的缩水甘油醛产量增加可能解释了环氧化物混合物致癌反应的增强。
