HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/6/E1764    most recent 00525.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Marini, J. C. Articles by Lee, B. Search for Related Content PubMed PubMed Citation Articles by Marini, J. C. Articles by Lee, B.

Interaction between murine spf-ash mutation and genetic background yields different metabolic phenotypes

¹USDA/ARS Children's Nutrition Research Center, Department of Pediatrics and ²Department of Molecular and Human Genetics, Baylor College of Medicine, and ³the Howard Hughes Medical Institute, Houston, Texas

Submitted 13 August 2007 ; accepted in final form 8 October 2007

The spf-ash mutation in mice results in reduced hepatic and intestinal ornithine transcarbamylase. However, a reduction in enzyme activity only translates in reduced ureagenesis and hyperammonemia when an unbalanced nitrogen load is imposed. Six-week-old wild-type control and spf-ash mutant male mice from different genetic backgrounds (B6 and ICR) were infused intravenously with [¹³C¹⁸O]urea, L-[¹⁵N₂]arginine, L-[5,5 D₂]ornithine, L-[6-¹³C, 4,4,5,5, D₄]citrulline, and L-[ring-D₅]phenylalanine to investigate the interaction between genetic background and spf-ash mutation on ureagenesis, arginine metabolism, and nitric oxide production. ICR^spf-ash mice maintained ureagenesis (5.5 ± 0.3 mmol·kg^–1·h^–1) and developed mild hyperammonemia (145 ± 19 µmol/l) when an unbalanced nitrogen load was imposed; however, B6^spf-ash mice became hyperammonemic (671 ± 15 µmol/l) due to compromised ureagenesis (3.4 ± 0.1 mmol·kg^–1·h^–1). Ornithine supplementation restored ureagenesis and mitigated hyperammonemia. A reduction in citrulline entry rate was observed due to the mutation in both genetic backgrounds (wild-type: 128, spf-ash: 60; SE 4.0 µmol·kg^–1·h^–1). Arginine entry rate was only reduced in B6^spf-ash mice (B6^spf-ash: 332, ICR^spf-ash: 453; SE 20.6 µmol·kg^–1·h^–1). Genetic background and mutation had an effect on nitric oxide production (B6: 3.4, B6^spf-ash: 2.8, ICR: 9.0, ICR^spf-ash: 4.6, SE 0.7 µmol·kg^–1·h^–1). Protein breakdown was the main source of arginine during the postabsorptive state and was higher in ICR^spf-ash than in B6^spf-ash mice (phenylalanine entry rate 479 and 327, respectively; SE 18 µmol·kg^–1·h^–1). Our results highlight the importance of the interaction between mutation and genetic background on ureagenesis, arginine metabolism, and nitric oxide production. These observations help explain the wide phenotypic variation of ornithine transcarbamylase deficiency in the human population.

arginine; nitric oxide; urea cycle

This article has been cited by other articles:

				Y. C. Luiking, M. M. Hallemeesch, M. C. van de Poll, C. H. C. Dejong, W. J. de Jonge, W. H. Lamers, and N. E. P. Deutz Reduced citrulline availability by OTC deficiency in mice is related to reduced nitric oxide production Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1315 - E1322. [Abstract] [Full Text] [PDF]