The influence of dietary restriction on the metabolism of theophylline and antipyrine in the ageing female BN/BiRij rat

K Groen, DD Breimer, A Brouwer, G Schijff, EJ Jansen and CF van Bezooijen

TNO Institute for Ageing and Vascular Research, Leiden, The Netherlands.

The influence of ageing and dietary restriction (DR) on the in vivo activities of different P450 enzymes was studied longitudinally in female BN/BiRij rats. For this purpose, antipyrine (AP) and theophylline (TH) were used as substrates. The metabolic clearances of AP (CIm AP) and TH (CIm TH) were used as indicators for P450 enzyme activities in vivo. Therefore, we also included the assessment of the clearances of formation of three AP metabolites, i.e., 3- hydroxymethylantipyrine (CI-->HMA), 4-hydroxyantipyrine (CI-->OHA) and norantipyrine (CI-->NORA). Ninety, 50 and 10% survival times were prolonged significantly in DR rats. In control animals, the contribution to the metabolism of AP in the formation of HMA, OHA and NORA, expressed as percentage of the dose, decreased with ageing, indicating that other pathways compensate for this decrease. Only a significant decrease in the metabolism to OHA was observed in DR animals. CI-->HMA, CI-->OHA and CI-->NORA showed an age-related decrease in the control rats, whereas in the DR rats an age-related decrease was observed for CI-->HMA and CI-->OHA. The results of the present study suggest that the decrease in the activities of the P450 enzymes involved in the formation of HMA, OHA and NORA have a later onset in the DR rats. In conclusion, DR not only has a strong positive influence on the health and life span of the rats, but also results in a delayed onset of the decrease in activity of certain P450 enzymes.

Volume 274, Issue 1, pp. 143-147, 07/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics