Competition for polyamine uptake into rat lung slices by WR2721 and analogues.
The objective of these studies was to determine whether a series of structurally related radioprotective agents could act as substrates for the recently identified polyamine system in the lung. We have shown that WR2721 (S-2(3-aminopropylamino)ethyl phosphorothioate), S-2(4-aminobutylamino)ethyl phosphorothioate (S-ABEP or WR2822) and S-2(7-aminoheptylamino)ethyl phosphorothioate (S-AHEP) competitively inhibit the uptake of putrescine into rat lung slices. The ability of the radioprotectors to act as substrates for the polyamine uptake system was expressed as the Ki for each compound. The Ki values for WR2721, S-ABEP and S-AHEP in the absence of dithiothreitol were 48, 57 and 7 mumol dm-3 compared to 155, 88 and 15 mumol dm-3 in the presence of dithiothreitol, indicating that the disulphide form may have a higher affinity for the transport system. By analogy with other substrates for the polyamine uptake system we have concluded that it should be possible to target radioprotectors to the alveolar epithelial type I and II cells and the Clara cells in the lung, as they prossess this uptake system, and thus protect these cells from oxidative stress.
Wyatt
I
I
Biochemical Toxicology Section, ICI Central Toxicology Laboratory, Cheshire, U.K.
Moore
R B
RB
Smith
L L
LL
D004999:Amifostine / Q000493:pharmacokinetics*; D000818:Animals; D005260:Female; D008168:Lung / Q000378:metabolism*; D009946:Organothiophosphorus Compounds / Q000493:pharmacokinetics*; D011073:Polyamines / Q000493:pharmacokinetics*; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
D009946:Organothiophosphorus Compounds; D011073:Polyamines; D011837:Radiation-Protective Agents; C058738:S-(2-((aminoheptyl)amino)ethyl)phosphorothiate; C035282:S-(2-((4-aminobutyl)amino)ethyl)phosphorothioate; D004999:Amifostine