D. F. Evered, H. Selhi
Feb 1, 1972
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Journal
The Biochemical journal
Abstract
Hydroxyurea has numerous biochemical and biological effects, including the inhibition of DNA synthesis (Brachet, 1967), and also has anti-tumour properties (Steams et al., 1963). Hadacidin (Nformylhydroxyaminoacetic acid) suppresses growth of human adenocarcinoma in vitro (Gitterman et al., 1962). It is an aspartate analogue inhibiting reversibly the enzyme adenylosuccinate synthetase (Shigeura & Gordon, 1962). We investigated the transport of these potentially therapeutic compounds across the mucosa of the rat small intestine in vitro. Either everted sacs (Randall & Evered, 1964) or everted segments (Wass & Evered, 1970) were used. Neither hydroxyurea (assay method: Nery, 1966) nor hadacidin (assay method: Iqbal & Ottaway, 1970) was transferred across everted sacs against a concentration gradient. The concentration ratio (serosal concn./mucosal concn.) was, for 5imMhydroxyurea, 0.97T0.02S.E.M. (16 sacs), and, for 5mM hadacidin, 0.87±0.09S.E.M. (16 sacs). Transport of hydroxyurea with the concentration gradient was linear over the range 2-15mm external concentration. This transfer was not diminished by the presence of 1 mM-KCN. Similarly, hadacidin transport down the gradient with everted sacs gave linear kinetics over the range 3-20mM. Uptake of hadacidin (1 mM) by intestinal sacs and segments was not inhibited by 1 mmor 10mM-KCN, methionine, L-aspartate, glycine, betaine, L-proline or L-hydroxyproline. The result with hydroxyurea is not unexpected, since urea (Jervis & Smyth, 1959) and thiourea (Esposito et al., 1969) both show simple diffusion across the intestine. At 5mM hadacidin did not show active transport with everted sacs (Spencer & Brody, 1964), but the lack of inhibition by structurally related analogues or a metabolic inhibitor has not previously been demonstrated. Our results all suggest that hydroxyurea and hadacidin pass across the mucosa of the rat small intestine by simple diffusion.