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The effect of age upon the affinity of microsomal mono-oxygenase enzymes for substrate in human liver
H A Wynne1, E Mutch, O F James
1Department of Medicine (Geriatrics), University of Newcastle upon Tyne.
Abstract:
Although the clearance of many oxidized drugs falls with age, a corresponding fall in the maximal activities of drug metabolizing enzymes has not been noted. The possibility of a fall in enzyme affinity for substrate with age, which could account for the observed changes, has not previously been investigated in human liver. We have studied the kinetics of the microsomal mono-oxygenase 7-ethoxycoumarin-O-de-ethylase in 17 human liver biopsy specimens. No correlation was observed between age and microsomal protein recovery, maximal enzyme activity or apparent enzyme affinity. Since microsomal mono-oxygenase activities and affinities appear not to change in human liver, other factors such as a fall in liver volume or blood flow must be responsible for the decline in clearance of many oxidized drugs which occurs with ageing.
Insights
Drug clearance decreases with age, but enzyme activity in human liver does not. This study found no age-related changes in enzyme affinity, suggesting other factors like reduced liver size or blood flow impact drug metabolism.
Area of Science:
- Pharmacology
- Gerontology
- Biochemistry
Background:
- Drug clearance often declines in older adults.
- Maximal drug-metabolizing enzyme activities typically remain unchanged with age.
- The impact of aging on enzyme-substrate affinity in human liver is not well understood.
Purpose of the Study:
- To investigate whether enzyme affinity for substrates decreases with age in human liver.
- To examine the kinetics of microsomal mono-oxygenase 7-ethoxycoumarin-O-de-ethylase in relation to age.
Main Methods:
- Studied the kinetics of 7-ethoxycoumarin-O-de-ethylase in 17 human liver biopsy specimens.
- Analyzed correlations between age and enzyme activity, affinity, and protein recovery.
Main Results:
- No significant correlation was found between age and microsomal protein recovery.
- Maximal enzyme activity showed no age-dependent decline.
- Apparent enzyme affinity for the substrate did not correlate with age.
Conclusions:
- Enzyme activity and affinity of microsomal mono-oxygenase do not appear to change with age in the human liver.
- The decline in drug clearance with aging is likely due to factors other than altered enzyme kinetics, such as reduced liver volume or blood flow.