Taylor M J, Lucier G W, Mahler J F, Thompson M, Lockhart A C, Clark G C
Syntex Research, Palo Alto, California 94303.
Toxicol Appl Pharmacol. 1992 Nov;117(1):126-32. doi: 10.1016/0041-008x(92)90227-j.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) acute toxicity is characterized in part by a wasting syndrome with depletion of adipose tissue. Tumor necrosis factor (TNF) induces a similar response during chronic infection. The similarities of these toxic effects led to a hypothesis that TNF plays a role in TCDD acute toxicity. To test this hypothesis pharmacologic doses of an antibody specific for murine TNF and the potent anti-inflammatory agent Dexamethasone (DEX) were used to inhibit TCDD toxicity in mice. TNF antibody treatment resulted in a 54% reduction in TCDD-mediated mortality while DEX treatment, a glucocorticoid agonist that inhibits transcription of TNF, reduced mortality by 92%. Cyp 1A1 induction, the most commonly measured TCDD-mediated response, was not blocked by DEX, demonstrating separation of this biochemical effect from acute toxic responses to TCDD. These data suggest that TCDD-mediated changes in the TNF pathway may be an important mechanism for acute TCDD toxicity.
2,3,7,8-四氯二苯并对二噁英（TCDD）的急性毒性部分表现为一种伴有脂肪组织消耗的消瘦综合征。肿瘤坏死因子（TNF）在慢性感染期间会引发类似反应。这些毒性作用的相似性导致了一种假说，即TNF在TCDD急性毒性中发挥作用。为了验证这一假说，使用了针对小鼠TNF的特异性抗体的药理剂量以及强效抗炎剂地塞米松（DEX）来抑制小鼠体内的TCDD毒性。TNF抗体治疗使TCDD介导的死亡率降低了54%，而DEX治疗（一种抑制TNF转录的糖皮质激素激动剂）使死亡率降低了92%。细胞色素P450 1A1（Cyp 1A1）诱导是最常检测的TCDD介导的反应，它并未被DEX阻断，这表明这种生化效应与对TCDD的急性毒性反应是分离的。这些数据表明，TCDD介导的TNF途径变化可能是TCDD急性毒性的重要机制。
