Soni M G, Mehendale H M
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505.
Toxicol Appl Pharmacol. 1991 Mar 15;108(1):46-57. doi: 10.1016/0041-008x(91)90267-i.
Chlordecone (CD) pretreatment is well known to greatly potentiate CCl4 toxicity. Previous work has shown that suppression of hepatocellular regeneration permits an ordinarily limited liver injury to progress in an irreversible manner. Insufficient hepatocellular energy has been proposed as a mechanism for suppressed hepatocellular regeneration. Since cyanidanol reportedly increases cellular ATP, this compound was employed to test the above hypothesis. The present study was designed to investigate the sequential biochemical and histological changes over a time course of 120 hr after CCl4 administration. Male Sprague-Dawley rats (125-150 g) were maintained on 10 ppm CD diet for 15 days and were challenged with either a standard protocol dose (100 microliters/kg) or a low (50 microliters/kg, L) dose of CCl4. Cyanidanol pretreatment at 48, 24, and 2 hr before CCl4 administration to rats maintained on CD diet resulted in 100 or 70% animal survival, for CCl4 (L) or the standard dose of CCl4, respectively. Preliminary studies indicated that neither simultaneous nor subsequent administration of cyanidanol with CCl4 challenge affords such protection. Prior treatment with cyanidanol and a latency period were found necessary for protection. Without cyanidanol, CD + CCl4 combination caused 50 and 100% lethality after CCl4 (L) and the standard dose, respectively, while the same doses of CCl4 alone did not cause lethal effects. Plasma enzymes (alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase) in control rats showed only moderate and transient increases after CCl4 challenge. The combination of CD + standard dose of CCl4 resulted in progressive and marked elevations of all three serum enzymes at all time intervals until the death of animals. Cyanidanol pretreatment resulted in significant decline in the plasma enzyme elevations at later time points. Cyanidanol pretreatment increased hepatic ATP synthesis in control or CD rats. CCl4 administration to control rats did not alter hepatic ATP levels, while in CD-fed rats hepatic ATP levels were significantly decreased. Cyanidanol pretreatment to CD + CCl4 combination-treated rats did not significantly prevent the decline in hepatic ATP and glycogen levels. However, in the surviving rats a recovery in these parameters was observed. Light microscopic examination of livers from animals that received CCl4 alone revealed only marginal cellular injury, at early time points only. However, CCl4 challenge to rats maintained on CD resulted in progressive injury, characterized by the appearance of ballooned cells, necrotic cells, and cells with lipid droplets in the liver. Cyanidanol pretreatment to these rats caused decreased vacuolation and significantly reduced the progression of liver necrosis.(ABSTRACT TRUNCATED AT 400 WORDS)
众所周知，开蓬（CD）预处理可极大地增强四氯化碳（CCl₄）的毒性。先前的研究表明，肝细胞再生的抑制会使原本有限的肝损伤以不可逆的方式进展。有人提出肝细胞能量不足是肝细胞再生受抑制的一种机制。由于据报道氰定醇可增加细胞内三磷酸腺苷（ATP），因此使用该化合物来验证上述假设。本研究旨在调查给予CCl₄后120小时内的一系列生化和组织学变化。将雄性斯普拉格 - 道利大鼠（125 - 150克）饲养在含10 ppm CD的饲料中15天，然后用标准方案剂量（100微升/千克）或低剂量（50微升/千克，L）的CCl₄进行攻击。在给食用CD饲料的大鼠注射CCl₄前48小时、24小时和2小时进行氰定醇预处理，对于CCl₄（L）或标准剂量的CCl₄，动物存活率分别为100%或70%。初步研究表明，氰定醇与CCl₄攻击同时或随后给药均不能提供这种保护。发现用氰定醇预先处理并经过一段潜伏期对于保护是必要的。没有氰定醇时，CD + CCl₄组合在给予CCl₄（L）和标准剂量后分别导致50%和100%的致死率，而相同剂量的CCl₄单独使用不会产生致死效果。对照大鼠中的血浆酶（丙氨酸氨基转移酶、天冬氨酸氨基转移酶、山梨醇脱氢酶）在CCl₄攻击后仅显示中度和短暂升高。CD + 标准剂量的CCl₄组合在所有时间间隔都导致所有三种血清酶逐渐且显著升高，直至动物死亡。氰定醇预处理导致后期血浆酶升高显著下降。氰定醇预处理增加了对照或CD大鼠肝脏中的ATP合成。给对照大鼠注射CCl₄不会改变肝脏ATP水平，而在食用CD的大鼠中肝脏ATP水平显著降低。对CD + CCl₄组合处理的大鼠进行氰定醇预处理并不能显著阻止肝脏ATP和糖原水平的下降。然而，在存活的大鼠中观察到这些参数有所恢复。对仅接受CCl₄的动物肝脏进行光镜检查发现，仅在早期时间点有轻微的细胞损伤。然而，对食用CD的大鼠进行CCl₄攻击会导致进行性损伤，其特征是肝脏中出现气球样细胞、坏死细胞和含脂滴的细胞。对这些大鼠进行氰定醇预处理可减少空泡形成，并显著减轻肝坏死的进展。（摘要截取自400字）
