Aging Aging

Xenobiotic-Metabolizing Enzymes 125tein to which drugs bind, decrease in the aged, presumably the consequence ofreduced synthesis, leading to lower protein binding.In animal studies, it was repeatedly shown that the metabolism of manyxenobiotics declines in old age, resulting in prolongation of the pharmacologicaleffect of drugs (16,17). However, evidence for reduced capacity in the metabolismof drugs through cytochrome P450 catalyzed pathways is lacking (18). Itis also feasible that the various cytochrome P450 proteins respond differently tothe onset of old age, but this remains to be investigated. In studies carried out inmale rats, aged between 1 wk and 2 yr, cytochrome P450 activity was investigatedby determining the hydroxylation of testosterone at different positionsand was complemented by immunological determination of the apoprotein levels(19). It was evident that age-dependent changes differed among the cytochromeP450 enzymes studied. For example, hepatic levels of CYP2C11disappeared in old age whereas CYP2A1 levels increased and those of CYP2E1were unaffected.The recent availability of in vivo probes displaying selectivity for specificcytochrome P450 forms has made it possible to assess the effect of age on cytochromeP450 expression in humans. The N-demethylation of erythromycin,a diagnostic probe for CYP3A4, the major cytochrome P450 enzyme in thehuman liver, was determined by measuring the amount of carbon dioxideexhaled. No difference was detectable between healthy aged volunteers(age ranging between 70 and 88 yr) in comparison to younger adults (age rangingbetween 20 and 60), showing that the expression of CYP3A is not affectedby age in humans (20). Similarly, the expression of CYP2E1 was constant inhumans aged between 30 and 75 yr of age (21). In more recent studies, employingas probes lignocaine (CYP3A4) and coumarin (CYP2A6), a decrease wasreported in the levels of these drugs with increasing age (22). In these studiesthe authors compared healthy young volunteers (65 yr). Similarly, in recent extensive studies, the half-life of antipyrine,a drug whose metabolism involves a number of cytochrome P450 proteins,increased in the elderly whereas its clearance decreased (23). Clearly, theeffect of age on individual cytochrome P450 enzymes is far from being understood,and it is only now that such studies are being undertaken. It must beemphasized that the old consume a disproportionate number of drugs comparedwith other subpopulations and an understanding of their ability to handledrugs will lead to more effective treatment.1.5. Measurement of Cytochrome P450 Activitiesin Human Liver Using AlkoxyresorufinsIn 1974, Burke and Mayer (24) demonstrated that an alkoxyphenoxazonederivative, ethoxyresorufin, could be metabolized by CYP1A1 with a high