Abstract

The pyrrolizidine alkaloid monocrotaline (MCT) has been shown to cause hepatic necrosis and pulmonary hypertension in the rat. To better understand the mechanism of action, tissue distribution and covalent binding studies were conducted at 4 and 24 hr following administration of [14C]MCT (60 mg/kg, 200 microCi/kg, sc). For the 4 hr study, the levels of MCT equivalents were 85, 74, 67, 36, and 8 nmol/g of tissue for red blood cells (RBC), liver, kidney, lung, and plasma, respectively, while the covalent binding levels were 125, 132, 39, 64, 44 pmol/mg of protein for tissues as listed above. The 24-hr tissue distribution levels were 49, 25, 9, 10, 2 nmol/g of tissue for RBC, liver, kidney, lung, and plasma, respectively, while covalent binding was 74, 28, and 55 pmol/mg of protein for liver, kidney, and lung, respectively. We also studied the kinetics of [14C]MCT (60 mg/kg, 10 microCi/kg, iv), which demonstrated rapid elimination of radioactivity with approximately 90% recovery of the injected radioactivity in the urine and bile by 7 hr. The plasma levels of radioactivity dropped from 113 nmol/g of MCT equivalents to 11 nmol/g at 7 hr while RBC levels decreased from 144 to only 81 nmol/g at the same time point. The apparent retention of MCT equivalents in the RBC suggests that this organ may act as the carrier of metabolites from the liver to other organs including the lung and may play a role in the pulmonary toxicity.