Reichl F X, Szinicz L, Kreppel H, Forth W
Walther Straub-Institut für Pharmakologie und Toxikologie der Ludwig-Maximilians-Universität München, Federal Republic of Germany.
Arch Toxicol. 1989;63(5):419-22. doi: 10.1007/BF00303134.
Differences in the metabolite pattern were observed in previous experiments in guinea pig livers after a single injection or prolonged (5 days) treatment with AS2O3 (Reichl et al. 1988). To elucidate the underlying mechanism the effect of As2O3 on liver metabolism was therefore investigated. Male guinea pigs received either a single dose (s.d.) of As2O3 10 mg x kg-1 s.c. or repeated doses (r.d.) of 2.5 mg x kg-1b.i.d. on 5 consecutive days. One hour after the s.d. or 1 h and 16 h after the last injection in the r.d. groups the animals were sacrificed in anaesthesia. The livers were removed by freeze clamping for the determination of various metabolites. In the s.d. group a significant decrease in hydroxybutyrate, acetylCoA, adenosinemonophosphate and in the ratio of hydroxybutyrate/acetoacetate and an increase in pyruvate, citrate, malate, and adenosinetriphosphate were observed. A significant decrease in glycogen, pyruvate, alpha-ketoglutarate, acetylCoA, and acetoacetate and a significant increase in malate and in the ratios of lactate/pyruvate and hydroxybutyrate/acetoacetate were observed in the r.d.1-h group. In the r.d.16-h group a significant decrease in glycogen, pyruvate, lactate, and adenosinemonophosphate was found, but the values tended towards control values. The data are consistent with mechanisms of As2O3 toxicity in other species as PDH inhibition with consecutive citric acid cycle and gluconeogenesis inhibition and excessive carbohydrate depletion.
在先前的实验中，观察到豚鼠肝脏在单次注射或用三氧化二砷（AS2O3）进行延长（5天）治疗后代谢物模式存在差异（Reichl等人，1988年）。因此，为了阐明潜在机制，研究了三氧化二砷对肝脏代谢的影响。雄性豚鼠接受单次剂量（s.d.）的10mg/kg三氧化二砷皮下注射，或连续5天每天两次重复剂量（r.d.）的2.5mg/kg。单次注射后1小时或重复剂量组最后一次注射后1小时和16小时，动物在麻醉状态下处死。通过冷冻钳夹取出肝脏以测定各种代谢物。在单次剂量组中，观察到羟基丁酸、乙酰辅酶A、单磷酸腺苷以及羟基丁酸/乙酰乙酸的比率显著降低，而丙酮酸、柠檬酸、苹果酸和三磷酸腺苷增加。在重复剂量1小时组中，观察到糖原、丙酮酸、α-酮戊二酸、乙酰辅酶A和乙酰乙酸显著降低，苹果酸以及乳酸/丙酮酸和羟基丁酸/乙酰乙酸的比率显著增加。在重复剂量16小时组中，发现糖原、丙酮酸、乳酸和单磷酸腺苷显著降低，但这些值趋于接近对照值。这些数据与三氧化二砷在其他物种中的毒性机制一致，即抑制丙酮酸脱氢酶，随后抑制柠檬酸循环和糖异生，并导致碳水化合物过度消耗。
