Dose-response relationship in intoxication by the pyrrolizidine alkaloid monocrotaline.
Dose-response relationship in intoxication by the pyrrolizidine alkaloid monocrotaline.
复制标题
吡咯里西啶生物碱野百合碱中毒的剂量-反应关系。
DOI：
10.1080/15287398909531363
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Huxtable,RJ
中科院分区：
文献类型：
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作者：
Shubat,PJ;Hubbard,AK;Huxtable,RJ
大鼠连续摄入溶于饮用水（20 mg/l）的野百合碱2周后发生肺动脉高压。通过给雄性大鼠（初始体重100 g）饮用水中的野百合碱（5、10、20、40或60 mg/l），持续0、1、2、4、6、10或20 d，研究野百合碱浓度与暴露时间的关系。在开始治疗后20天处死大鼠，测量肺和右心室与体重的比率增加作为肺动脉高压的指标。使用浓度为10 mg/l（18 mg/kg）的饮用水在10天内输送的野百合碱累积剂量产生的右心室肥大和肺重量增加程度与饮用20或40 mg/l野百合碱水（14和29 mg/kg）的大鼠在4天内摄入的剂量相同。苯巴比妥预处理并没有实质性地改变20毫克/升野百合碱水诱导的毒性的时间过程。连续1d灌胃60 mg/L野百合碱（11 mg/kg），20 d时右心室肥厚。由于低于11 mg/kg的累积剂量不会产生毒性，而高于14 mg/kg的所有剂量都会产生毒性，因此可将该范围视为诱导毒性的阈值。然而，阈值暴露后器官重量增加在4周内逆转。肺动脉壁厚度的增加与右心室肥厚的发展相关。肺部炎症不是野百合碱给药的早期反应，因为在野百合碱治疗的前6天，肺灌洗液中回收的细胞类型比例没有变化。
Rats develop pulmonary hypertension over a 2‐wk period of continuous ingestion of monocrotaline dissolved in drinking water (20 mg/l). The relationship between monocrotaline concentration and duration of exposure was investigated by giving male rats (initial body weight 100 g) monocrotaline in drinking water (5,10, 20, 40, or 60 mg/l) for 0, 1, 2, 4, 6, 10, or 20 d. Rats were killed 20 d after initiating treatment, and increased lung and right ventricular to body weight ratios were measured as indices of pulmonary hypertension. The accumulative dose of monocrotaline delivered over a 10‐d period using a drinking water concentration of 10 mg/l (18 mg/kg) produced the same degree of right ventricular hypertrophy and lung weight increases as the doses ingested over a 4‐d period by rats consuming 20 or 40 mg/l monocrotaline water (14 and 29 mg/kg). Phenobarbital pretreatment did not substantially alter the time course of toxicity induced with 20 mg/l monocrotaline water. Ingestion of 60 mg/l monocrotaline water for 1 d (11 mg/kg) resulted in right ventricular hypertrophy at 20 d. Since accumulative doses of less than 11 mg/kg did not produce toxicity and all doses greater than 14 mg/kg did, this range may be considered a threshold for inducing toxicity. However, organ weight increases following threshold exposures reversed over a 4‐wk period. Increases in the wall thickness of pulmonary arteries correlated with the development of right ventricular hypertrophy. Pulmonary inflammation was not an early response to monocrotaline administration, since there was no change in the proportion of cell types recovered in lung lavage fluid during the first 6 d of monocrotaline treatment.