The importance of epithelial uptake systems in lung toxicity.
The discovery that the herbicide paraquat was selectively accumulated by the lung, both in vivo and in vitro, in comparison with other tissues, provided an explanation for its selective toxicity to the lung. This uptake process is energy dependent and obeys saturation kinetics. A characterization of the process led to the identification of endogenous chemicals that are the natural substrates for the system. Among these are a series of diamines and polyamines, as well as the diaminodisulfide cystamine. It appears that paraquat, because of specific structural similarities to these endogenous polyamines, is mistakenly accumulated by the lung. This uptake process is specifically located in the alveolar Type II cell, the Clara cell, and probably the alveolar Type I cell. With the development of knowledge of the structural requirements of chemicals to be accumulated by this system, it is possible to predict which chemicals will be accumulated by the lung or design molecules that are targeted to the alveolar epithelial and Clara cells. In the wider perspective, this polyamine uptake system has been found on a number of cancerous cells or tissues. With the knowledge of the uptake system in the lung, it should be possible to design drugs that will be specifically concentrated in cells that possess this system.
ICI Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
L L
LL
Smith
C P
CP
Lewis
I
I
Wyatt
G M
GM
Cohen
D000818:Animals; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D010269:Paraquat / Q000493:pharmacokinetics* / Q000633:toxicity; D011073:Polyamines / Q000493:pharmacokinetics*; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats
D011073:Polyamines; D010269:Paraquat