Chengelis C P, Dodd D C, Means J R, Kotsonis F N
Fundam Appl Toxicol. 1986 Feb;6(2):278-84. doi: 10.1016/0272-0590(86)90241-1.
The purpose of this investigation was to assess protection by zinc against acetaminophen induced hepatotoxicity and to evaluate possible mechanisms of protection. Mice were treated with zinc (3 mg/kg, ip) or saline (ip) 48 and 24 hr before and sacrificed 12 hr after acetaminophen administration (375, 500, or 750 mg/kg, po). Liver toxicity was then assessed by histological examination. The incidence of hepatotoxicity was significantly less at 375 and 500 mg/kg of acetaminophen in zinc treated animals. The same dosage of zinc was not hepatoprotective when given 1 hr after acetaminophen. Mice were also treated with 1 to 10 mg/kg of zinc (ip) 48 and 24 hr prior to sacrifice, and metallothionein, cytochrome P-450, glutathione, and UDP-glucuronosyl transferase (GT) were determined in the liver. Metallothionein and UDP-GT were increased and P-450 and glutathione decreased at the higher dosages of zinc; however, only metallothionein was significantly changed at the dosage of zinc (3 mg/kg) used in the hepatoprotection experiments. Further, mice were similarly treated with 3 mg/kg of zinc before administration of 375 mg/kg of [3H]acetaminophen (po) and the amount of acetaminophen and acetaminophen bound to metallothionein were determined in the liver for 0.5 to 24 hr. In addition, after 6 hr the subcellular distribution and covalent binding to protein of acetaminophen were also determined. Zinc treatment had no significant effect in any of the above determinations. These results indicate that zinc protects against acetaminophen induced hepatotoxicity and that the observed protection is probably due to an induced biochemical change, but it is apparently not the result of any of the commonly invoked mechanisms.
本研究的目的是评估锌对乙酰氨基酚诱导的肝毒性的保护作用，并探讨可能的保护机制。在给予乙酰氨基酚（375、500或750 mg/kg，口服）前48小时和24小时，给小鼠腹腔注射锌（3 mg/kg）或生理盐水，给药后12小时处死小鼠。然后通过组织学检查评估肝毒性。在锌处理的动物中，375和500 mg/kg剂量的乙酰氨基酚所致肝毒性的发生率显著降低。在乙酰氨基酚给药后1小时给予相同剂量的锌则无肝保护作用。在处死前48小时和24小时，给小鼠腹腔注射1至10 mg/kg的锌，然后测定肝脏中的金属硫蛋白、细胞色素P-450、谷胱甘肽和尿苷二磷酸葡萄糖醛酸转移酶（GT）。在较高剂量的锌作用下，金属硫蛋白和UDP-GT增加，P-450和谷胱甘肽减少；然而，在肝保护实验中使用的锌剂量（3 mg/kg）下，只有金属硫蛋白有显著变化。此外，在给予375 mg/kg [3H]乙酰氨基酚（口服）前，给小鼠同样注射3 mg/kg的锌，然后在0.5至24小时内测定肝脏中乙酰氨基酚的含量以及与金属硫蛋白结合的乙酰氨基酚的量。另外，6小时后还测定了乙酰氨基酚的亚细胞分布及其与蛋白质的共价结合情况。锌处理在上述任何测定中均无显著影响。这些结果表明，锌可保护机体免受乙酰氨基酚诱导的肝毒性，观察到的保护作用可能是由于诱导的生化变化，但显然不是任何常见机制作用的结果。
