Palkar Prajakta S, Philip Binu K, Reddy Ramesh N, Mehendale Harihara M
Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, 700 University Avenue, Sugar Hall # 306, Monroe, LA 71209-0495, USA.
Toxicol Appl Pharmacol. 2007 Nov 15;225(1):102-12. doi: 10.1016/j.taap.2007.06.011. Epub 2007 Jun 30.
Protection against a high dose of a toxicant by prior exposure to another toxicant is called heteroprotection. Our objective was to establish a heteroprotection model in RBCs. Female Sprague Dawley rats treated with an LD90 dose of 2-butoxyethanol (BE, 1500 mg/kg in water, 5 ml/kg po) 14 days after priming with 0.9% NaCl suffered 90% mortality by 15 days, whereas all rats receiving the LD90 dose of BE 14 days after priming with phenylhydrazine (PHZ, 125 mg/kg in 0.9% NaCl, 3 ml/kg po) survived. Hematocrit decreased from normal 45% to 24% by day 3 after PHZ priming and improved thereafter. Increasing the time interval between the priming and LD90 dose to 21 days abolished the heteroprotection. RBCs obtained on days 7 and 14 after PHZ priming unlike those on day 21 were resilient to the hemotoxic metabolite of BE, butoxyacetic acid (BAA). Unaltered hepatic alcohol and aldehyde dehydrogenase activities upon PHZ priming suggested that bioactivation of BE to BAA was unaffected. Lower renal (6 and 12 h) and hepatic (12 h) BAA levels and 3 fold higher excretion of BAA in PHZ-primed rat urine suggested a protective role of toxicokinetics. Higher erythropoietin, reticulocytes, and resiliency of PHZ-primed rat RBCs indicated that newly formed RBCs are resilient to hemolytic BAA. The antioxidant levels in the PHZ-primed rat RBCs did not indicate a protective role in heteroprotection. In conclusion, the resistance of PHZ-primed rats against BE-induced hemotoxicity and lethality is mediated by a combination of altered toxicokinetics, robust erythropoiesis, and resiliency of new RBCs.
预先接触一种毒物可对高剂量的另一种毒物产生保护作用，这种现象称为异源保护。我们的目标是在红细胞中建立一种异源保护模型。用0.9%氯化钠溶液预处理的雌性斯普拉格-道利大鼠，在预处理14天后给予LD90剂量的2-丁氧基乙醇（BE，1500毫克/千克溶于水，5毫升/千克口服），到15天时死亡率达90%，而在用苯肼（PHZ，125毫克/千克溶于0.9%氯化钠溶液，3毫升/千克口服）预处理14天后给予LD90剂量BE的所有大鼠均存活。PHZ预处理后第3天，血细胞比容从正常的45%降至24%，此后有所改善。将预处理与LD90剂量之间的时间间隔增加到21天，异源保护作用消失。PHZ预处理后第7天和第14天获得的红细胞，与第21天获得的红细胞不同，对BE的血液毒性代谢产物丁氧基乙酸（BAA）具有抗性。PHZ预处理后肝醇脱氢酶和醛脱氢酶活性未改变，表明BE向BAA的生物活化未受影响。PHZ预处理大鼠的肾脏（6小时和12小时）和肝脏（12小时）BAA水平较低，且尿液中BAA排泄量高3倍，提示毒物代谢动力学起保护作用。PHZ预处理大鼠红细胞中促红细胞生成素、网织红细胞水平较高且具有抗性，表明新生成的红细胞对溶血的BAA具有抗性。PHZ预处理大鼠红细胞中的抗氧化剂水平在异源保护中未显示出保护作用。总之，PHZ预处理大鼠对BE诱导的血液毒性和致死性的抗性是由毒物代谢动力学改变、强大的红细胞生成以及新红细胞的抗性共同介导的。
