AJP - Gastrointestinal and Liver Physiology, Vol 249, Issue 6 792-G799, Copyright © 1985 by American Physiological Society
Inhibition of intestinal citrulline synthesis causes severe growth retardation in rats
N. Hoogenraad, N. Totino, H. Elmer, C. Wraight, P. Alewood and R. B. Johns
delta-N-(phosphonacetyl)-L-ornithine (PALO) is a powerful and specific
inhibitor of ornithine transcarbamylase (1), but it does not readily enter
intact cells and therefore does not inhibit citrulline synthesis in intact
liver or intestine. We have used the glycylglycine derivative of PALO
(Gly-Gly-PALO) to evaluate the importance of intestinal citrulline
synthesis in supplying arginine for growth. We have shown that the peptide
derivative of PALO is selectively taken up by gut cells via the peptide
permease and is released intracellularly as the free inhibitor. When
administered in drinking water to 6-wk-old rat pups on an
arginine-deficient diet, serum citrulline was reduced from 85 +/- 4.2 to 44
+/- 2.2 microM and arginine from 240.1 +/- 19.0 to 52.1 +/- 4.1 microM.
Ornithine increased from 100 +/- 6.2 to 273.5 +/- 21.3 microM. Addition of
0.1 mM Gly-Gly-PALO to drinking water caused a rapid and complete
inhibition of growth in rats on arginine-deficient diets, and this growth
inhibition could be partially prevented by simultaneous administration of
1% (wt/wt) arginine to the diet and completely prevented with 1% (wt/wt)
citrulline. The specificity of the effects of Gly-Gly-PALO on intestinal
citrulline synthesis was shown by the inability of the drug to be taken up
or to inhibit citrulline synthesis in isolated rat hepatocytes, and the
oral administration of the drug had no effect on serum ammonia
concentrations. The relative importance of endogenous synthesis of arginine
compared with dietary arginine for growth was shown by the ability of
Gly-Gly-PALO to inhibit the growth of rats maintained on standard
laboratory chow containing normal levels of arginine.
