Some Aspects of Ammonia Toxicity in Animal Cells

Abstract

Ammonia is produced by metabolic processes in cells and is a substance to which cells of all phylogenetie levels are accustomed (25, 100). Despite its constant presence in living protoplasm, ammonia can produce deleterious effects which are well known to many areas of biology and medicine. These harmful effects a r e believed to arise from the action of ammonia at intracellular sites, and may become manifest : a) when normal detoxifieation processes a r e impaired as by disease, b) when ammonia is introduced too rapidly, e) when the quantities of ammonia are excessive, or d) when the form of ammonia introduced is highly toxic. Since entry of ammonia into cells appears to be prerequisite for its toxicity, penetration of cell membranes by ammonia has been studied under a variety of circumstances. Such studies have employed blossoms of rhododendron, starfish eggs, erythrocytes (37, 38), peach t r e e s (15), fish (19), the mammalian kidney (57, 60, 63), and intact animals (33, 43, 94, 97). The data obtained have permitted the formulation of some general theories regarding the behavior of ammonia in biological systems which are pertinent to problems of intoxication arising from incorporation of non-protein nitrogen (NPN) in animal diets. Mammals and birds have efficient systems for excreting ammonia or converting it to nontoxic end products (4). Not only does ammonia arise from body tissues but also from bacterial enzymes acting upon nitrogenous substrafes in the lumen of the alimentary tract. The alimentary tract is the major source of ammonia outside of the tissues, and in conventional animals hydrolysis of endogenous urea is believed to be the major source of ammonia liberated by bacteria (22, 61, 77, 85, 93). Portal vein blood contains ammonia concentrations which a r e s e v e r a l times those of the peripheral arterial or venous blood (22, 51, 68). One passage of blood through the normal liver removes virtually all of the ammonia delivered from the intestines. Even with 70% of the liver removed mammals can tolerate concentrations o£ blood ammonia which are fa r in excess of those found under conditions of normal metabolism (35). Peripheral and cerebral uptake of ammonia is known to occur (6, 7, 81), and it is well recognized that shunting of blood past the liver to the systemic eirculation leads to neurological complications which are readily reproduced by administration of ammonia or other nitrogenous substances (61, 75, 76). Such shunting occurs in liver cirrhosis, an important cause of morbidity and nortal i ty in man. Many investigations have been carried out since the beginning of this century in attempts to understand cirrhosis and the syndrome of portohepatoencephalopathy commonly referred to as hepatic coma. Ammonia is one, if not the pr imary toxin which can precipitate this syndrome (76). Diseases of the kidney, an important site of ammonia production, lead to elevations in blood of nonprotein nitrogen. Thus, extensive research has also emphasized the renal metabolism of ammonia and the pathogenesis of uremia (74). Much of the experimental work on all forms of ammonia intox~ica tion has been done in animals.