Model-based compartmental analysis indicates a reduced mobilization of hepatic vitamin A during inflammation in rats

Sin H. Gieng, Michael H. Green, Joanne B. Green, and Francisco J. Rosales

Discovery, Mead Johnson Nutritionals, Evansville, Indiana 47721

Corresponding Author: francisco.rosales{at}bms.com

Vitamin A (VA) kinetics was studied in rats with marginal hepatic VA stores before, during, and after inflammation-induced hyporetinolemia. Rats received an oral dose of [3H]VA (d 0), and inflammation was induced on d 21 with lipopolysacchride (LPS) for 3 d (n=5) or recombinant human interleukin-6 (rhIL-6) for 7 d (n=5); PBS was similarly given to controls (n=4). Plasma samples were serially collected from 2 h to 54 d after [3H]VA administration, and retinol concentrations and radioactivity were measured. Both the fraction of [3H]VA and retinol concentrations in plasma were significantly reduced by LPS or rhIL-6. Compartmental analysis using the Windows version of the Simulation, Analysis, and Modeling software was applied to group mean data to develop non-steady-state models of VA kinetics. Following absorption of the oral dose, VA kinetics before, during and after inflammation was adequately described by a three-compartment model that included plasma, kidney/interstitium and liver/carcass. Four potential mechanisms responsible for inflammation-induced hyporetinolemia were investigated: increased urinary excretion, increased irreversible loss, increased movement into interstitial fluid, and decreased hepatic mobilization of retinol. Modeling results indicated that a 79 % reduction in mobilization of hepatic retinol (from 4.3 to 0.9 nmol/h) by 15 h after LPS administration best accounted for observed changes in plasma VA kinetics (sum of squares= 9.05x10-07). rhIL-6 caused a similar but earlier reduction (75% by 5.6 h lasting for up to 8 d). The models predict that, after inflammation, hepatic retinol mobilization returned to control values by 10 d. Inflammation-induced hyporetinolemia, if prolonged, can render hepatic retinol unavailable to extra-hepatic tissues, possibly leading to their impaired function as observed in VA-deficient children with measles virus infection.

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to Technorati Technorati What's this?

This article has been cited by other articles:

C. J. Cifelli, J. B. Green, Z. Wang, S. Yin, R. M. Russell, G. Tang, and M. H. Green
Kinetic Analysis Shows that Vitamin A Disposal Rate in Humans Is Positively Correlated with Vitamin A Stores
J. Nutr., May 1, 2008; 138(5): 971 - 977.
[Abstract] [Full Text] [PDF]

All ASBMB Journals	Journal of Biological Chemistry
Molecular and Cellular Proteomics	ASBMB Today