Kim S K, Kim Y C, Kim Y C
College of Pharmacy, Seoul National University, Korea.
Food Chem Toxicol. 1998 Aug;36(8):655-61. doi: 10.1016/s0278-6915(98)00024-6.
Effects of a single dose of betaine on the chloroform-induced hepatotoxicity were examined in adult male ICR mice. Administration of betaine (1000 mg/kg, ip) 1 to 7 hr prior to a chloroform challenge (0.25 ml/kg, ip) resulted in remarkable enhancement of hepatotoxicity as indicated by increases in serum sorbitol dehydrogenase (SDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. The potentiation of hepatotoxicity was most significant when mice were treated with betaine 4 hr earlier than chloroform. However, a 24 hr prior administration of betaine protected the animals from induction of the chloroform hepatotoxicity. Thus, its effect appeared to be highly dependent on the time lapse from the betaine pretreatment to the challenge of mice with chloroform. Betaine treated either 4 or 24 hr prior to sacrifice did not alter the hepatic contents of cytochrome P-450, cytochrome b5, or NADPH cytochrome P-450 reductase activity. Accordingly the hepatic microsomal p-nitroanisole O-demethylase, aminopyrine N-demethylase, or p-nitrophenol hydroxylase activities were not influenced by the betaine pretreatment. Betaine was shown not to affect any of the enzyme activities associated with glutathione (GSH) conjugation reaction, such as glutathione S-transferases (GSTs), glutathione disulfide (GSSG) reductase and GSH peroxidase irrespective of the time of its administration. When betaine was administered to mice 2-6 hr prior to sacrifice, hepatic GSH level, but not plasma GSH, was decreased significantly. Enhancement of the chloroform hepatotoxicity by betaine correlated well with the reduction in hepatic GSH levels. Both hepatic and plasma GSH levels were elevated in mice 24 hr following the betaine treatment. The results suggest that betaine affects induction of the chloroform hepatotoxicity by modulating the availability of hepatic GSH, which appears to be associated with its role in the transsulfuration pathway in the liver.
在成年雄性ICR小鼠中研究了单剂量甜菜碱对氯仿诱导的肝毒性的影响。在氯仿激发（0.25 ml/kg，腹腔注射）前1至7小时给予甜菜碱（1000 mg/kg，腹腔注射），结果血清山梨醇脱氢酶（SDH）、丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）活性增加，表明肝毒性显著增强。当小鼠在氯仿处理前4小时用甜菜碱处理时，肝毒性的增强最为显著。然而，提前24小时给予甜菜碱可保护动物免受氯仿肝毒性的诱导。因此，其作用似乎高度依赖于从甜菜碱预处理到用氯仿激发小鼠的时间间隔。在处死前4或24小时用甜菜碱处理均未改变细胞色素P-450、细胞色素b5的肝脏含量或NADPH细胞色素P-450还原酶活性。因此，肝脏微粒体对硝基苯甲醚O-脱甲基酶、氨基比林N-脱甲基酶或对硝基苯酚羟化酶活性不受甜菜碱预处理的影响。结果表明，无论给药时间如何，甜菜碱均不影响与谷胱甘肽（GSH）结合反应相关的任何酶活性，如谷胱甘肽S-转移酶（GSTs）、谷胱甘肽二硫化物（GSSG）还原酶和GSH过氧化物酶。当在处死前2至6小时给小鼠注射甜菜碱时，肝脏GSH水平显著降低，但血浆GSH水平未降低。甜菜碱对氯仿肝毒性的增强与肝脏GSH水平的降低密切相关。甜菜碱处理24小时后，小鼠肝脏和血浆GSH水平均升高。结果表明，甜菜碱通过调节肝脏GSH的可用性来影响氯仿肝毒性的诱导，这似乎与其在肝脏转硫途径中的作用有关。
