Pohjanvirta R, Sankari S, Kulju T, Naukkarinen A, Ylinen M, Tuomisto J
National Public Health Institute, Department of Environmental Hygiene and Toxicology, Kuopio, Finland.
Pharmacol Toxicol. 1990 May;66(5):399-408. doi: 10.1111/j.1600-0773.1990.tb00769.x.
Lipid peroxidation has been shown to be enhanced following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but its role in TCDD toxicity is unclear. The present study was undertaken to further elucidate the relations between lipid peroxidation and TCDD lethality. A time course and dose-response experiment in Long-Evans (L-E; LD50 ca. 10 micrograms/kg) and Han/Wistar (H/W; LD50 greater than 3000 micrograms/kg) rats showed that hepatic lipid peroxidation, measured as the amount of thiobarbituric acid-reactive substances (TBA-RS), was induced by TCDD dose-dependently in L-E, but not in H/W rats. Hepatic glutathione peroxidase activity was suppressed in much the same manner in both strains. Lipid peroxidation correlated with body weight loss in L-E rats alone. When 500 micrograms/kg of TCDD was given to L-E rats, lipid peroxidation increased about 3-fold on Day 11 in the liver, while no change was seen in cardiac or renal TBA-RS. The pair-fed controls did not survive the 11-day test period and exhibited gastrointestinal hemorrhages. At 6 days, liver atrophy and elevated (over 2-fold) TBA-RS values were recorded in pair-fed controls but not in their TCDD-treated counterparts. TCDD decreased hepatic glutathione peroxidase activity by almost 50% at 6 days, while pair-feeding was without effect. Liver morphology was different between TCDD-treated and pair-fed rats. Moreover, the livers of TCDD-treated L-E rats contained much higher concentrations of probably peripheral fat-derived fatty acids than did the livers of pair-fed or ad libitum control rats. Restricted feeding over 6 days induced hepatic lipid peroxidation more in H/W than in L-E rats. Endotoxin increased liver TBA levels similarly in both strains having an additive effect with high doses of TCDD in H/W rats. Added as a 0.5% concentration in chow, butylated hydroxyanisole (BHA), but not ethoxyquin, tended to increase survival rate and time in L-E rats exposed to 20 micrograms/kg of TCDD; at 50 micrograms/kg the only survivor was again in the BHA group. However, neither antioxidant had any effect on initial body weight loss. It is concluded that lipid peroxidation mainly arises as a secondary phenomenon in TCDD toxicity, is not the cause of the typical histopathological liver lesion, but may contribute to lethality.
已表明，暴露于2,3,7,8-四氯二苯并-对-二噁英（TCDD）后脂质过氧化作用增强，但其在TCDD毒性中的作用尚不清楚。本研究旨在进一步阐明脂质过氧化与TCDD致死性之间的关系。在长-伊文斯（L-E；半数致死量约为10微克/千克）和汉/威斯塔（H/W；半数致死量大于3000微克/千克）大鼠中进行的时间进程和剂量反应实验表明，以硫代巴比妥酸反应性物质（TBA-RS）的量来衡量，肝脂质过氧化在L-E大鼠中呈剂量依赖性地被TCDD诱导，但在H/W大鼠中则不然。两种品系的肝谷胱甘肽过氧化物酶活性均以大致相同的方式受到抑制。脂质过氧化仅与L-E大鼠的体重减轻相关。当给L-E大鼠给予500微克/千克的TCDD时，肝脏中的脂质过氧化在第11天增加了约3倍，而心脏或肾脏中的TBA-RS未见变化。成对喂食的对照组在11天的试验期内未存活，并出现胃肠道出血。在第6天，成对喂食的对照组出现肝脏萎缩且TBA-RS值升高（超过2倍），而接受TCDD处理的大鼠则未出现。TCDD在第6天将肝谷胱甘肽过氧化物酶活性降低了近50%，而成对喂食则无此作用。TCDD处理组和成对喂食组大鼠的肝脏形态不同。此外，接受TCDD处理的L-E大鼠肝脏中可能来自外周脂肪的脂肪酸浓度远高于成对喂食或随意进食对照组大鼠的肝脏。在6天内限制喂食在H/W大鼠中比在L-E大鼠中更易诱导肝脂质过氧化。内毒素在两种品系中均以类似方式增加肝脏TBA水平，在H/W大鼠中与高剂量TCDD具有相加作用。在饲料中添加0.5%浓度的丁基羟基茴香醚（BHA）而非乙氧喹，倾向于提高暴露于20微克/千克TCDD的L-E大鼠的存活率和存活时间；在50微克/千克时，唯一的存活者再次出现在BHA组。然而，两种抗氧化剂对初始体重减轻均无任何影响。结论是，脂质过氧化主要作为TCDD毒性中的一种继发现象出现，不是典型肝组织病理学病变的原因，但可能对致死性有影响。
