Hayashi F, Tamura H, Yamada J, Kasai H, Suga T
Department of Clinical Biochemistry, Tokyo College of Pharmacy, Japan.
Carcinogenesis. 1994 Oct;15(10):2215-9. doi: 10.1093/carcin/15.10.2215.
The characteristics of the hepatocarcinogenesis induced by dehydroepiandrosterone (DHEA) were compared with that induced by other peroxisome proliferators such as [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) and di(2-ethylhexyl)phthalate (DEHP). Male F-344 rats were given a diet containing DHEA at 0.5 or 1%, Wy-14,643 at 0.1% and DEHP at 2% for up to 78 weeks. In rats fed 0.5 or 1% DHEA the incidence of neoplasias was 20% after 52 weeks. At 78 weeks all rats treated with 1% DHEA had numerous grossly visible nodules and the incidence of hepatic neoplasia was dose-dependent. The magnitude of hepatocellular tumorigenicity after DHEA treatment was less potent than that after Wy-14,643, but more than that after DEHP treatment. Peroxisomal beta-oxidation activity increased three- or six-fold after a 10 week course of 0.5 or 1% DHEA respectively and this was significantly lower than that induced in Wy-14,643- or DEHP-fed rats. From 52 to 78 weeks these activities increased 3-9 times over that in controls. In both the group of rats treated with Wy-14,643 and those treated with DEHP, peroxisomal beta-oxidation constantly increased 11- to 15-fold during the experiment. Catalase activity increased 1.3- to 1.5-fold for the first 10 weeks of DHEA treatment and then recovered to the control level. The activities of glutathione peroxidase and glutathione S-transferase decreased markedly after 30 weeks in DHEA-treated rats and the decreases were sustained for up to 78 weeks. The profile of changes in enzyme activities in the rats fed DHEA was not significantly different from that of those fed Wy-14,643 or DEHP. There were no increases in 8-hydroxydeoxyguanosine, oxidative DNA damage or lipid peroxide level in the liver in any of the treated rats at 10 or 30 weeks. Since these results showed that the characteristics of hepatocarcinogenesis caused by DHEA were basically similar to those caused by Wy-14,643 and DEHP, typical peroxisome proliferators, hepatocarcinogenesis induced by DHEA is probably due to the same mechanisms as that induced by general peroxisome proliferators.
将脱氢表雄酮（DHEA）诱导的肝癌发生特征与其他过氧化物酶体增殖剂如[4-氯-6-(2,3-二甲基苯胺基)-2-嘧啶硫代]乙酸（Wy-14,643）和邻苯二甲酸二(2-乙基己基)酯（DEHP）诱导的肝癌发生特征进行了比较。给雄性F-344大鼠喂食含0.5%或1% DHEA、0.1% Wy-14,643和2% DEHP的饮食，持续78周。在喂食0.5%或1% DHEA的大鼠中，52周后肿瘤发生率为20%。在78周时，所有接受1% DHEA治疗的大鼠都有许多肉眼可见的结节，肝肿瘤发生率呈剂量依赖性。DHEA治疗后肝细胞致瘤性的程度低于Wy-14,643治疗后，但高于DEHP治疗后。分别给予0.5%或1% DHEA 10周后，过氧化物酶体β-氧化活性增加了3倍或6倍，这明显低于喂食Wy-14,643或DEHP的大鼠。从52周到78周，这些活性比对照组增加了3 - 9倍。在接受Wy-14,643治疗的大鼠组和接受DEHP治疗的大鼠组中，在实验过程中过氧化物酶体β-氧化活性持续增加11至15倍。在DHEA治疗的前10周，过氧化氢酶活性增加了1.3至1.5倍，然后恢复到对照水平。在DHEA治疗的大鼠中，30周后谷胱甘肽过氧化物酶和谷胱甘肽S-转移酶的活性显著下降，并且这种下降持续到78周。喂食DHEA的大鼠中酶活性变化的情况与喂食Wy-14,643或DEHP的大鼠没有显著差异。在10周或30周时，任何治疗组的大鼠肝脏中8-羟基脱氧鸟苷、氧化性DNA损伤或脂质过氧化物水平均未增加。由于这些结果表明DHEA引起的肝癌发生特征与典型的过氧化物酶体增殖剂Wy-14,643和DEHP引起的基本相似，DHEA诱导的肝癌发生可能与一般过氧化物酶体增殖剂诱导的肝癌发生机制相同。
