Inhibition by piroxicam of oxidative DNA damage, liver cirrhosis and development of enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats
Inhibition by piroxicam of oxidative DNA damage, liver cirrhosis and development of enzyme-altered nodules caused by a choline-deficient, L-amino acid-defined diet in rats
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DOI：
10.1093/carcin/18.10.1921
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发表时间：
1997-10-01
期刊：
影响因子：
4.7
通讯作者：
Konishi, Y
中科院分区：
文献类型：
--
作者：
Denda, A;Endoh, T;Konishi, Y
先前，我们报道了阿司匹林，一种环氧化酶（COX）抑制剂，可以预防大鼠胆碱缺乏，l -氨基酸定义（CDAA）饮食引起的纤维化，肝硬化和氧化DNA损伤的产生，以及谷胱甘肽- s -转移酶胎盘形式（GST-P）阳性肿瘤前肝结节的相关发展。在本研究中，为了阐明COX途径在CDAA饮食诱导肝脏病变中的作用，研究了其他不同化学类别的COX抑制剂的调节作用。以CDAA喂养F344雄性大鼠，给予长效吡罗西康（PIRO）（剂量分别为0.01、0.02、0.04和0.06%）、短效布洛芬（IBU）（剂量分别为0.02、0.04和0.06%）和吲哚美辛（IND）（剂量分别为0.005和0.008%），分别于12周和30周后处死。在另一项实验中，在饮用水中添加了剂量分别为0.001、0.002%和0.004%的IND。没有一种抑制剂影响CDAA饮食引起的脂肪肝的发展，但PIRO在剂量高于0.04%时，强烈抑制gst -p阳性和肿瘤结节的发展以及纤维化、肝硬化和8-羟基脱氧鸟苷（8-OHdG）加合物的形成。IBU在最高剂量下也表现出类似但不那么明显的抑制作用。对于IND，只有抑制倾向，没有明显的剂量依赖性。这些结果与我们之前的研究结果一起表明，相对强的COX抑制剂，如阿司匹林的不可逆作用或如PIRO的长时间作用，可以防止与CDAA饮食相关的内源性肝癌的发生，尽管不是脂肪肝的发展，这表明增强的COX途径可能在该模型中肝脏病变的原因中起关键作用。
Previously, we have reported that aspirin, a cyclooxygenase (COX) inhibitor, can prevent the fibrosis, cirrhosis and generation of oxidative DNA damage, and the associated development of glutathione-S-transferase placental form (GST-P)-positive preneoplastic liver nodules, caused by a choline-deficient, L-amino acid-defined (CDAA) diet in rats. In the present study, in order to elucidate the role of COX pathway in liver lesion-induction by a CDAA diet, the modulatory effects of other distinct chemical classes of COX inhibitors were examined. A long-acting example, piroxicam (PIRO) (at doses of 0.01, 0.02, 0.04 and 0.06%) and the short-acting ibuprofen (IBU) (at doses of 0.02, 0.04 and 0.06%) and indomethacin (IND) (at doses of 0.005 and 0.008%) were administered in the CDAA diet to male F344 rats, and animals were killed after 12 and 30 weeks. In another experiment, IND was given in drinking water at doses of 0.001, 0.002 and 0.004%. None of the inhibitors affected the development of fatty liver caused by a CDAA diet, but PIRO at doses higher than 0.04%, strongly inhibited the development of GST-P-positive and neoplastic nodules as well as fibrosis, cirrhosis and formation of 8-hydroxydeoxyguanosine (8-OHdG) adducts. IBU at the highest dose also exhibited similar but much less pronounced inhibitory effects. With IND, there was only a tendency for inhibition with no clear dose-dependence. The results together with our previous findings, indicate that relatively strong COX inhibitors, acting irreversibly like aspirin or for extended periods like PIRO, can prevent the endogenous hepatocarcinogenesis associated with a CDAA diet, although not the development of a fatty liver, suggesting that an augmented COX pathway might play key roles in the causation of liver lesions in this model.