MATHEMATICAL-MODELING AND ANALYSIS OF GLUCOSE AND GLUTAMINE UTILIZATION AND REGULATION IN CULTURES OF CONTINUOUS MAMMALIAN-CELLS

A number of factors have been shown to affect the metabolism of glucos e and glutamine in mammalian cells and their mechanisms have been part ially elucidated. Despite these efforts, a quantitative knowledge of t he significance of these factors, the regulation of glucose and glutam ine utilization, and particularly the interactions of these two nutrie nts is still lacking. Controversies exist in the literature. To clarif y some of these controversies, mathematical models are proposed in thi s work which enable to separate and identify the effects of individual factors. Experimental data from five cell lines obtained in batch, fe d-batch, and continuous cultures, both under steady-state and transien t conditions, were used to verify the model formulations. The resultin g kinetic models successfully describe all these cultures. According t o the models, the specific consumption rate of glucose (q(Glc)) of con tinuous animal cells under normal culture conditions can be expressed as a sum of three parts: a part owing to cell growth; a part owing to glucose excess; and a part owing to glutamine regulation. The specific consumption rate of glutamine (q(Gln)) can be expressed as a sum of o nly two parts: a part owing to cell growth; and a part: owing to gluta mine excess. Using the kinetic models the interaction and regulation o f glucose and glutamine utilizations are quantitatively analyzed. The results indicate that, whereas q(Glc) is affected by glutamine, q(Gln) appears to be not or less significantly affected by glucose. It is al so shown that the relative utilizations of glucose and glutamine by an abolism and catabolism are mainly affected by the residual concentrati ons of the respective compounds and are less sensitive to growth rate and the nature of growth limitation. (C) 1995 John Wiley and Sons, Inc .