The effect of age on mono-oxygenase enzyme kinetics in rat liver microsomes

The clearance of many oxidized drugs falls with age. Whilst factors such as reduced liver size, blood flow and specific enzyme activity may be important, the possibility that reduced enzyme affinity for substrate contributes to this fall has not hitherto been investigated. Using liver microsomes from 12 young adult and 12 elderly male Norwegian Brown rats we defined the kinetics of ethoxyresorufin-O-de-ethylation and aldrin epoxidation, specific substrates for the 3-methylcholanthrene inducible and phenobarbitone inducible forms of cytochrome P450, respectively. Our results show a marked fall in the maximal activity of both enzymes in advanced age whether expressed in terms of microsomal protein or unit of cytochrome P450, but with no change in apparent enzyme affinity (Km). Since Km is unchanged, we feel that qualitative age-related changes in cytochrome P450 are unlikely. Reduced metabolism may be due to age-related alterations in coenzymes or smooth endoplasmic reticulum lipid membranes.