Young Scientists Award Lecture 1981: The Identification of an Accumulation System for Diamines and Polyamines Into the Lung and Its Relevance to Paraquat Toxicity

Abstract

The energy dependent accumulation of the herbicide paraquat into the lung is known to be a major factor responsible for the selective toxicity of paraquat to this organ. The studies reported in this paper were designed to examine the hypothesis that the transport process responsible for the accumulation of paraquat is present to accumulate endogenous substrates from the plasma. Paraquat is accumulated into the lung by a process which is different from that responsible for the uptake of the monoamine, 5-hydroxytryptamine (5HT). Furthermore, 5HT is known to be accumulated into the endothelial cells of the lung whereas paraquat was accumulated, at least in part, by the alveolar type I and type II epithelial cells. In the search for compounds which would reduce the uptake of paraquat into the lung a series of diamines were found to be the most effective inhibitors. In particular the diamine, putrescine, effectively inhibited the uptake of paraquat into the lung and was itself accumulated by a process which obeyed saturation kinetics. The apparent Km for the process was 7.tM with a Vmax of 330 µmoles/g wet weight lung/h. This apparent Km is an order of magnitude lower than that for the uptake of paraquat. The uptake of putrescine was inhibited when paraquat was present in the incubation medium or when the metabolic inhibitors rotenone, or iodoacetate together with KCN were added. Putrescine was not accumulated by slices of liver, kidney, heart or spleen. It was taken up into brain slices by a KCN sensitive process although the accumulation was much less than that which occurred in lung slices. Thus, in these respects the uptake of putrescine is similar to that which has been described for paraquat. The uptake of putrescine into lung slices with damaged type I and type II alveolar epithelial cells was reduced as was the uptake of paraquat. The reduction was similar for both compounds suggesting they were both taken up into the same cellular compartment. The studies described in this paper suggest that (i) the process in the lung which accumulates paraquat is that which is normally responsible for the uptake of putrescine in particular and endogenous diamines and polyamines in general and (ii) this uptake process is located in the alveolar type I and type II epithelial cells.