The 26th International Symposium on Microsomes and Drug Oxidations

Background: In humans, CYP2A6, the principal enzyme for coumarin and nicotine metabolism, shows wide interindividual genetic variation and environmental regulation, complicating the determination of age- and sex-related differences. African green monkeys, with comparable CYP2A6 activity to humans, were used to investigate age- and sex-effects on CYP2A6 activity.
Methods: Liver and body weights were recorded, and microsomal protein content was assessed by cytochrome P450 oxidoreductase activity assay. Liver microsomes were prepared from AGMs (N=56) across five developmental stages. Microsomes were used to measure 7-hydroxycoumarin and cotinine formation from coumarin and nicotine, respectively. Significant differences (p<0.05) were determined using two-way ANOVA.
Results: There was a significant age effect for microsomal protein content, while liver and body weight exhibited significant age and sex differences, with age by sex interactions. Pooled microsomes per age-sex group were used to determine the kinetic parameters for 7-hydroxycoumarin and cotinine formation. Significant age effects were observed for the velocity of 7-hydroxycoumarin and cotinine formation (individual monkeys assessed at substrate concentrations of ~Km and ~10x Km), expressed per milligram microsomal protein (V_mic) and per gram liver (V_{g liver}), which were larger for cotinine formation: juvenile and adolescent monkeys had higher velocities. When scaled to whole liver (V_{whole liver}), 7-hydroxycoumarin and cotinine formation showed significant age and sex differences, with no interactions: older monkeys and males had higher velocities.
Conclusions: Together, CYP2A6 activity (V_mic) was faster in younger monkeys; however, once extrapolating to the whole liver, which increased with age, the V_{whole liver} were higher in older monkeys and males.