ANIMAL-MODEL FOR THE STUDY OF METHANOL TOXICITY - COMPARISON OF FOLATE-REDUCED RAT RESPONSES WITH PUBLISHED MONKEY DATA
ANIMAL-MODEL FOR THE STUDY OF METHANOL TOXICITY - COMPARISON OF FOLATE-REDUCED RAT RESPONSES WITH PUBLISHED MONKEY DATA
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DOI：
10.1080/15287399409531827
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发表时间：
1994-01-01
期刊：
影响因子：
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通讯作者：
TERZO, TS
中科院分区：
文献类型：
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作者：
LEE, EW;GARNER, CD;TERZO, TS
我们试图建立一种啮齿动物模型，该模型表现出人类甲醇中毒的特征，如酸中毒和视觉功能障碍，这些特征与甲醇的有毒代谢物甲酸盐的积累有关。首先，制备三组不同水平的Long-Evans大鼠肝脏叶酸，并检测甲醇(3.5g/kg)后的甲酸蓄积。用1%的琥珀酸磺胺噻唑喂养叶酸缺乏饮食的叶酸减少(FR)大鼠产生的血液甲酸盐水平相当于甲醇中毒的人类，并出现了视觉系统毒性的迹象(关于后者的手稿正在准备中)。然后研究了FR大鼠对各种甲醇暴露情景的反应，并将结果与猴子的文献报道进行了比较。甲酸蓄积和/或致死率被用作毒性参数进行比较评估。灌胃给药3g/kg的FR大鼠24 h血甲酸盐浓度为9.2 mmo1/L，48 h升至15.6 mmo1/L，给药12 h后，恒河猴血甲酸盐浓度平台为7.4 mmo1/L，并持续12h，血甲酸盐浓度-时间曲线下面积为2.0g/kg时的2.5倍。在1200ppm和2000ppm甲醇暴露6h后，FR大鼠的血甲酸盐浓度分别比内源性水平高出370%和636%。在急性吸入条件下，暴露于3000ppm甲醇20h/d的FR大鼠存活时间不超过4d，而暴露在3000ppm甲醇21h/d的猕猴存活时间超过20d，即使在10000ppm甲醇暴露后存活时间也超过4d。因此，这些结果表明，FR大鼠对甲醇的挑战比猴子更敏感，并表明FR大鼠可能是评估甲醇对人类健康影响的理想动物模型。
We attempted to develop a rodent model that exhibits characteristics of human methanol toxicities such as acidosis and visual dysfunction, which are correlated with an accumulation of formate, a toxic metabolite of methanol. Initially three groups of Long-Evans rats with different levels of liver folate were prepared and examined for formate accumulation after methanol administration (3.5 g/kg). The folate-reduced (FR) rats prepared by feeding a folate-deficient diet with 1 % succinylsulfathiazole yielded blood formate levels equivalent to those found in methanol-intoxicated humans and developed signs of the visual system toxicity (a manuscript on the latter aspect is in preparation). Responses of FR rats to a variety of methanol exposure scenarios were then investigated, and the results were compared with those reported in the literature for monkeys. Formate accumulation and/or lethality were used as toxic parameters for this comparative evaluation. In FR rats dosed orally with 3 g/kg, the blood formate concentration was 9.2 mmol/L at 24 h postadministration and increased to 15.6 mmol/l at 48 h. The same dose given to monkeys yielded a plateau of 7.4 mmol/L at 12 h after methanol administration, and stayed at this level for an additional 12 h. The area under the concentration vs. time curve for blood formate in FR rats was 2.5-fold greater than that in monkeys when 2.0 g/kg methanol was administered. After a 6-h exposure to 1200 ppm and 2000 ppm methanol, the blood formate concentrations in FR rats were increased by 370% and 636% above the endogenous level, respectively. However, blood formate did not accumulate above the endogenous level when monkeys were exposed to methanol up to 2000 ppm for 6 h. Under acute inhalation exposure conditions, FR rats exposed to 3000 ppm methanol, 20 h/d, could not survive more than 4 d. On the other hand, monkeys exposed to 3000 ppm, 21 h/d, outlived 20 d. Moreover, monkeys survived for more than 4 d even after an exposure to 10,000 ppm. Thus, these results indicate that FR rats are more sensitive to methanol challenges than monkeys, and suggest that the FR rat could be a congruous animal model for evaluating the health effects of methanol in humans.