ENSAT, Laboratoire de Toxicologie et Sécurité Alimentaire, Avenue de l'Agrobiopole, BP 107, 31326 Auzeville Tolosane Cedex, France.
Environ Toxicol Pharmacol. 1999 Apr;7(2):95-107. doi: 10.1016/s1382-6689(99)00008-3.
The roles of constitutive prostaglandin-H-synthetase (PGHS) and lipoxygenases in ochratoxin A (OTA) genotoxicity, as reflected by DNA adduct formation, have been investigated in vitro: (1) in culture of human epithelial cells and (2) by incubation in presence of pig seminal vesicle microsomes. Indomethacin (0.1 μM), which inhibits PGHS and significantly increases leukotriene C(4) production by enhancement of lipoxygenases, enhanced formation of OTA-DNA adducts tenfold. At highest dose of 10 μM, indomethacin inhibited all pathways (PGHS and lipoxygenases) and thus prevented OTA-DNA adduct formation. Nordihydroguaiaretic acid, which inhibits lipoxygenases, suppressed OTA-DNA adduct formation. The OTA metabolites formed were analysed by HPLC. OTα, 4[R]- and 4[S]-hydroxy-OTA and a unidentified derivative were formed in control cells. After pre-incubation with indomethacin (0.1 μM), further unidentified metabolites were obtained. They were similar to those obtained in presence of pig seminal vesicle microsomes. These data demonstrate that OTA is biotransformed into genotoxic metabolites via a lipoxygenase, whereas PGHS decreases OTA genotoxicity.
已在体外研究了结构型前列腺素 H 合酶 (PGHS) 和脂氧合酶在赭曲霉毒素 A (OTA) 遗传毒性中的作用，反映在 DNA 加合物的形成上：(1) 在人上皮细胞培养物中，和 (2) 在猪精囊微粒体孵育时。抑制 PGHS 并通过增强脂氧合酶显著增加白三烯 C(4) 产生的吲哚美辛 (0.1 μM) 使 OTA-DNA 加合物的形成增加了十倍。在最高剂量 10 μM 时，吲哚美辛抑制了所有途径 (PGHS 和脂氧合酶)，从而防止了 OTA-DNA 加合物的形成。抑制脂氧合酶的 Nordihydroguaiaretic acid 抑制了 OTA-DNA 加合物的形成。通过 HPLC 分析了形成的 OTA 代谢物。在对照细胞中形成了 OTα、4[R]-和 4[S]-羟基 OTA 和一种未鉴定的衍生物。在用吲哚美辛 (0.1 μM) 预孵育后，获得了进一步的未鉴定代谢物。它们与在猪精囊微粒体存在下获得的代谢物相似。这些数据表明，OTA 通过脂氧合酶生物转化为遗传毒性代谢物，而 PGHS 降低了 OTA 的遗传毒性。
