Abstract
Abstract
Several definitive statements concerning the effect(s) of animal age on liver drug metabolism are made, and at the same time certain crucial questions that remain to be resolved are posed. Between 16 and 30 months of age, or maturity and senescence, the male Fischer rat exhibits a significant loss of hepatic smooth-surfaced endoplasmic reticulum (SER) which constitutes a real quantitative change. However, this does not exclude the possibility of qualitative age-related changes in this membrane, such as compositional alterations which may be reflected in its functional integrity. Second, there is a significant decline in the noninduced activities or amounts of enzymes and hemoproteins, respectively, of the microsomal mixed function oxidase system. With the exception of the loss of cytochrome P-450, which represents a quantitative change, the age-dependent alterations in the two enzymes may reflect quantitative and/or qualitative changes. Last, the reduced hepatic responsiveness to phenobarbital is manifested not only in the slower rates of induction and the lower induced activities or amounts of these microsomal constituents, but also in the age-related declines in the hepatomegalic response and the induction of microsomal protein. The exact relationship between the phenobarbital-induced proliferation of the SER and the induction of drug-metabolizing enzymes as a function of age remains unclear. A sequential stereological analysis of the SER in response to phenobarbital in young, mature, and senescent animals may permit uncoupling of SER proliferation from enzyme induction and evaluation of the effect(s) of aging on each response separately.
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