title: A four-compartment compartmental model to assess net whole body protein breakdown using a pulse of phenylalanine and tyrosine stable isotopes in humans.
abstract: The stable isotopes of phenylalanine (Phe) and tyrosine (Tyr) are often used to study whole body protein metabolism in humans. Noncompartmental approaches give limited physiological insight in the compartmental characteristics. We therefore developed a compartmental mathematical model of Phe/Tyr metabolism to describe protein fluxes by using stable tracer dynamic data in plasma following intravenous bolus of l-[ring-13C6]Phe and l-[ring-2H4]Tyr in healthy subjects. The model consists of four compartments describing Phe/Tyr kinetics. Because the model is a priori nonidentifiable, it is quantified in terms of two uniquely identifiable submodels representing two limit case scenarios, based on known physiology. The two submodels, identified by using the software SAAM II, fit well the experimental data of all individuals and provide an unbiased overview of the metabolic pathway in terms of intervals of validity of the non-uniquely identifiable variables. The model provides estimates of the flux from Phe to Tyr [4.1 ± 1.0 µmol·kg fat-free mass (FFM)-1·h-1(mean ± SE)] and intervals of validity of the flux and pool estimates. Our preferred submodel yielded protein breakdown flux (50.5 ± 5.2 µmol·kg FFM-1·h-1), net protein breakdown (4.1 ± 1.0 µmol·kg FFM-1·h-1), Tyr from Phe hydroxylation (~12%), hydroxylated Phe (~8%), and flux ratio of Tyr to Phe arising from protein catabolism (0.68), consistent with available literature. The other submodel suggest that the assumptions made by noncompartmental analysis are consistently underestimated. Our accurate and detailed model for estimating Phe/Tyr metabolic pathways in humans might be essential to applications in a variety of scenarios describing whole body protein synthesis and breakdown in health and disease.
authors.affiliation: Center for Translational Research in Aging & Longevity, Department of Health and Kinesiology, Texas A&M University, College Station, Texas.|Department of Information Engineering, Universita' degli Studi di Padova, Padua, Italy; and.
authors.forename: Alvise
authors.initials: A
authors.lastname: Mason
authors.affiliation: Center for Translational Research in Aging & Longevity, Department of Health and Kinesiology, Texas A&M University, College Station, Texas.
authors.forename: Mariëlle P K J
authors.initials: MPKJ
authors.lastname: Engelen
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
authors.forename: Ivan
authors.initials: I
authors.lastname: Ivanov
authors.affiliation: Department of Information Engineering, Universita' degli Studi di Padova, Padua, Italy; and.
authors.forename: Gianna M
authors.initials: GM
authors.lastname: Toffolo
authors.affiliation: Center for Translational Research in Aging & Longevity, Department of Health and Kinesiology, Texas A&M University, College Station, Texas; nep.deutz@ctral.org.
authors.forename: Nicolaas E P
authors.identifier: 0000-0001-5845-6447
authors.initials: NEP
authors.lastname: Deutz
mesh_terms: D000368:Aged; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D064688:Metabolic Flux Analysis / Q000379:methods*; D008875:Middle Aged; D008954:Models, Biological; D010649:Phenylalanine / Q000493:pharmacokinetics*; D020543:Proteome / Q000378:metabolism*; D011865:Radioisotope Dilution Technique; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014443:Tyrosine / Q000493:pharmacokinetics*
chemical_list: D020543:Proteome; D019275:Radiopharmaceuticals; D014443:Tyrosine; D010649:Phenylalanine
keywords: compartmental model; parameter estimation; phenylalanine; stable isotopes; tracer kinetics; tyrosine