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Differential utilization of systemic and enteral ammonia for urea synthesis in control subjects and ornithine transcarbamylase deficiency carriers^1,2,3,4

¹ From the Department of Molecular and Human Genetics (FS, JH, and BL), the Department of Pediatrics (JR), Children’s Nutrition Research Center, and the Howard Hughes Medical Institute (BL), Baylor College of Medicine, Houston; the Department of Animal Sciences, University of Illinois-Urbana, Urbana, IL (JM and PR); and the Department of Surgery, Stony Brook University, Stony Brook, NY (PG).

Correspondence: ⁴ Address reprint requests to B Lee, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 630E, Houston, TX 77030. E-mail: blee{at}bcm.tmc.edu.

Background: Female carriers of ornithine transcarbamylase deficiency (OTCD) have nearly normal rates of total urea synthesis, but they derive less urea from systemic glutamine amide nitrogen than do healthy persons.

Objective: The objective of the study was to investigate whether females with symptomatic OTCD rely on alternative pathways to compensate for the reduced urea synthesis activity observed in this disorder.

Design: The 5-d study involved 6 control subjects (3 males, 3 females) and 6 female OTCD carriers who had a fixed energy intake of 133 kJ · kg^-1 · d^-1 and a protein intake of 0.8 g · kg^-1 · d^-1. They underwent two 12-h periods of isotopic tracer administration, separated by 2 d. On both occasions, [¹⁸O] or [¹³C]urea was infused intravenously, and the subjects consumed hourly meals. During the first period, [¹⁵N]NH₄Cl was given intravenously; during the second period, the tracer was given as hourly oral doses.

Results: OTCD carriers produced less urea (P < 0.05) but had a higher (P < 0.05) mean ammonia appearance rate and plasma ammonia concentration than did control subjects. OTCD carriers incorporated a lower (P < 0.001) mean (± SE) proportion of the intravenous [¹⁵N]NH₄Cl dose into circulating urea than did control subjects (16 ± 1% compared with 36 ± 2%), but there was no genotypic difference in the incorporation of orally administered tracer (81 ± 4% compared with 72 ± 4%, respectively).

Conclusion: A good degree of dietary protein tolerance seemed to be retained in OTCD carriers by the maintenance of higher ammonia appearance rates, expansion of the plasma ammonia pool, and reliance on the ability of the perivenous hepatocytes to clear excess ammonia via glutamine synthesis.

Key Words: Urea synthesis • humans • ammonia flux • ornithine transcarbamylase deficiency • stable isotopes

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