Page 1122 - Small Animal Clinical Nutrition 5th Edition

1168 Small Animal Clinical Nutrition

VetBooks.ir Box 68-2. Ammonia Metabolism and the Urea Cycle.

Ammonia is highly toxic and lethal. Therefore, excretion of excess at 20 to 50% capacity, allowing for adaptation to high or low pro-
ammonia is necessary for life. Animals have developed different tein foods. These mechanisms conserve nitrogen during periods of
approaches to this problem. Mammals use the urea cycle and glu- food deprivation, but slow the response time for ammonia detoxi-
tamine synthesis as ammonia disposal mechanisms. fication after ingestion of a high protein meal.
The amino acid intermediates used in the urea cycle (i.e.,
UREA SYNTHESIS ornithine, citrulline and arginine) are formed within the cycle itself
Urea is synthesized in the liver via the urea cycle (Figure 1). The and are provided by dietary sources of amino acids. In noncarniv-
initial step in urea production is synthesis of carbamoyl phosphate orous mammals, amino acids for the urea cycle can be synthesized
from bicarbonate and ammonia. Carbamoyl phosphate synthetase via alternative pathways; for example, rats can synthesize ornithine
I catalyzes carbamoyl phosphate formation in mitochondria. This via proline or glutamate, a process that doesn’t occur in obligate
reaction requires free Mg ++ and magnesium adenine triphos- carnivores. Therefore, noncarnivorous animals can better adapt to
phate, the rate-limiting step of the urea cycle. foods containing protein of lower quality that may not contain all of
Next, citrulline is formed from carbamoyl phosphate and the amino acids required for urea cycle function or foods that vary
ornithine. Ornithine transcarbamoylase, another mitochondrial in protein content over time.
enzyme, catalyzes this reaction.This step is followed by the cytoso-
lic portion of the urea cycle, beginning with a reaction catalyzed by THE UREA CYCLE IN CARNIVOROUS ANIMALS
argininosuccinate synthetase that combines citrulline with aspar- In contrast to noncarnivorous animals, carnivores (e.g., cats and
tate, a second nitrogen donor, to form argininosuccinate. Arg- ferrets) have not developed adaptive mechanisms to conserve
ininosuccinate is cleaved to arginine and fumarate via the action of nitrogen during periods of low protein intake. Only minimal
argininosuccinate lyase. Finally arginine is cleaved by arginase to changes in enzymatic activity are seen in cats fed either high or
form urea and ornithine. Urea is released into the circulation and low protein foods.Thus, urea cycle enzymes act continuously, inde-
ornithine reenters the urea cycle. pendent of dietary protein intake. Because enzymatic activity is
constant, carnivores control the urea cycle via concentrations of
THE UREA CYCLE IN NONCARNIVOROUS ANIMALS urea cycle intermediates, which allows for rapid detoxification of
In noncarnivorous mammals (i.e., herbivores and omnivores), the ammonia.
urea cycle is controlled by the activities of constituent enzymes, Carnivores are also unable to synthesize ornithine from proline
which in turn are controlled by the substrates they act upon. and glutamate.Therefore, ornithine for the urea cycle must be syn-
Additionally, during periods of normal protein intake, most enzymes thesized exclusively from arginine. Although the kidneys synthesize
involved in urea synthesis in noncarnivorous animals operate only a small amount of arginine from citrulline, the high activity of

Figure 2. The scavenger role of perivenous hepatocytes. Most
ammonia is metabolized to urea in the periportal hepatocytes.
Ammonia not metabolized to urea is metabolized to glutamine by
the perivenous hepatocytes (catalyzed by glutamine synthetase).
This prevents ammonia from entering the systemic circulation and
allows for uncoupling of urea production, which may be useful in
acid-base regulation. Key: CP = carbamoyl phosphate, Cit = cit-
Figure 1. General scheme of hepatic ammonia metabolism, illus-
rulline, Arg-Suc = argininosuccinate, Arg = arginine, Orn =
trating the pathways of ammonia usage (solid arrows) and ammo-
ornithine. (Adapted from Dimski DS. Ammonia metabolism and the
nia formation (broken arrows). (Adapted from Ampola MG. The
urea cycle: Function and clinical implications. Journal of Veterinary
urea cycle: Enzymes and defects. In: Arias IM, Boyer JL, Fausto
Internal Medicine 1994; 8: 75.)
N, et al, eds. The Liver: Biology and Pathobiology, 3rd ed. New
York, NY: Raven Press, 1994; 366.)