Pan L C, Wilson D W, Lamé M W, Jones A D, Segall H J
Department of Pharmacology and Toxicology, College of Veterinary Medicine, Davis, California.
Toxicol Appl Pharmacol. 1993 Jan;118(1):87-97. doi: 10.1006/taap.1993.1013.
Monocrotaline (MCT) produces pulmonary hypertension and right ventricular hypertrophy in rats. It is generally believed that MCT must undergo hepatic metabolism to reactive metabolites that are subsequently transported to the lungs to induce a pneumotoxic response. Several studies suggest that dehydromonocrotaline (MCTP) is the reactive intermediate that initiates pulmonary toxicity. We recently identified two other MCT metabolites, the glutathione and N-acetylcysteine conjugates of 6,7-dihydro-7-hydroxy-1-hydromethyl-5H-pyrrolizine (DHP). To determine the potential pulmonary toxicity of the glutathione conjugate (DHP-GSH) and the unacetylated cysteine conjugate precursor (DHP-Cys) of the N-acetylated excretion product, we conducted parallel in vivo toxicity studies with DHP-GSH, DHP-Cys, MCT, and MCTP. Relative pneumotoxicity was evaluated by measurements of right ventricular pressure (RVP), ventricular weight ratio (RV/LV+S), subjective histopathology, and measurements of components of the arteriolar wall. Animals given a single injection of MCT (60 mg/kg) developed pulmonary hypertension at the end of 3 weeks, as indicated by significant elevation in RVP when compared to the controls (22.1 +/- 2.4 mm Hg vs 13.2 +/- 0.8 mm Hg). A parallel and significant increase in RV/LV+S was also evident: 0.37 +/- 0.021 (MCT) vs 0.299 +/- 0.011 (control). Histopathology showed marked alterations in both pulmonary vasculature and parenchyma in MCT- and MCTP-treated animals. MCTP (1 mg/kg) caused a significantly elevated RVP (MCTP vs control: 28.1 +/- 3.4 mm Hg vs 16.8 +/- 0.97 mm Hg) and an increased RV/LV+S (MCTP vs control: 0.445 +/- 0.051 vs 0.284 +/- 0.026). Both MCT- and MCTP-treated rats had increased arteriolar medial thickness and decreased lumen diameter, but MCTP-treated rats had a milder vascular inflammatory response and less parenchymal lesions. Neither DHP-GSH (24 or 12 mg/kg) nor DHP-Cys (12 mg/kg) caused detectable changes in pulmonary circulation and no structural alteration in the lung was observed in these treatment groups. Although they are all pyrrolic metabolites of MCT, these studies demonstrate that only MCTP but not the glutathione or cysteine conjugates, is pneumotoxic at the doses tested.
野百合碱（MCT）可在大鼠中诱发肺动脉高压和右心室肥大。一般认为，MCT必须经过肝脏代谢生成活性代谢产物，这些代谢产物随后被转运至肺部以引发肺毒性反应。多项研究表明，脱氢野百合碱（MCTP）是引发肺毒性的活性中间体。我们最近鉴定出了另外两种MCT代谢产物，即6,7-二氢-7-羟基-1-羟甲基-5H-吡咯嗪（DHP）的谷胱甘肽和N-乙酰半胱氨酸共轭物。为了确定N-乙酰化排泄产物的谷胱甘肽共轭物（DHP-GSH）和未乙酰化的半胱氨酸共轭物前体（DHP-Cys）的潜在肺毒性，我们使用DHP-GSH、DHP-Cys、MCT和MCTP进行了平行的体内毒性研究。通过测量右心室压力（RVP）、心室重量比（RV/LV+S）、主观组织病理学以及小动脉壁成分的测量来评估相对肺毒性。单次注射MCT（60mg/kg）的动物在3周结束时出现了肺动脉高压，与对照组相比，RVP显著升高（22.1±2.4mmHg对13.2±0.8mmHg）。RV/LV+S也出现了平行且显著的增加：0.37±0.021（MCT）对0.299±0.011（对照组）。组织病理学显示，MCT和MCTP处理的动物的肺血管和实质均有明显改变。MCTP（1mg/kg）导致RVP显著升高（MCTP对对照组：28.1±3.4mmHg对16.8±0.97mmHg）以及RV/LV+S增加（MCTP对对照组：0.445±0.051对0.284±0.026）。MCT和MCTP处理的大鼠均出现小动脉中膜厚度增加和管腔直径减小，但MCTP处理的大鼠的血管炎症反应较轻且实质病变较少。DHP-GSH（24或12mg/kg）和DHP-Cys（12mg/kg）均未引起肺循环的可检测变化，并且在这些处理组中未观察到肺部结构改变。尽管它们都是MCT的吡咯代谢产物，但这些研究表明，在所测试的剂量下，只有MCTP具有肺毒性，而谷胱甘肽或半胱氨酸共轭物则没有。
