COR Pulmonale Is Caused by Monocrotaline and Dehydromonocrotaline, but Not by Glutathione or Cysteine Conjugates of Dihydropyrrolizine

Monocrotaline (MCT) produces pulmonary hypertension and right ventricular hypertrophy in rats. It is generally believed that MCI 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 MCI metabolites, the glutathione and N-acetylcysteine conjugates of 6,7-dihydro-7-hydroxy-I-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-GSI. DHP-Cys, MCI, 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 MCI (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 RVI LV + S was also evident: 0.37 ± 0.021 (MCI) vs 0.299 ± 0.011 (control). Histopathology showed marked alterations in both pulmonary vasculature and parenchyma in MCI- and MCIP-treated animals. MCIP (1 mg/kg) caused a significantly elevated RVP (MCIP vs control: 28.1 ± 3.4 mm Hg vs 16.8 ± 0.97 mm Hg) and an increased RV/LV + S (MCIP vs control: 0.445 ± 0.051 vs 0.284 ± 0.026). Both MCI- and MCIP-treated rats had increased arteriolar medial thickness and decreased lumen diameter, but MCIP-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 MCI, these studies demonstrate that only MCIP but not the glutathione or cysteine conjugates, is pneumotoxic at the doses tested.