A role for certain mouse Aprt sequences in resistance to toxic adenine analogs

The in vitro metabolic activity of the esterase responsible for the hydrolysis of diltiazem (DTZ) to its deacetylated metabolite (M1) was determined in an age-dependent fashion using the rabbit as an animal model. The presence of the enzyme in several tissues (liver, lung, small intestine, and brain) and in whole blood from pre-term and full-term fetuses, full-term newborns, yound and adult rabbits was examined. To this end, DTZ was spiked to 10,000-g tissue homogenates and whole blood to yield a final concentration of 1 microgram/ml. Serial samples were withdrawn from the incubation medium up to 240 min and assayed for DTZ and M1 concentration. In all tissues examined there was a net production of M1. Chemical breakdown and stability studies confirmed the metabolic origin of the M1 formed throughout the incubation. In pre-term fetuses (25 days of gestation) the brain was found to be the most active tissue in eliminating DTZ (brain > liver > lung > small intestine). This trend changed in young and adult rabbits (lung = brain > liver > small intestine). Although an important age-dependent DTZ deacetylase activity was observed in blood, it was not included in the comparison between organs because of the unequal composition of the incubation medium. In conclusion, results showed that fetuses and newborn rabbits have a similar, and in some instances higher, DTZ deacetylase activity to that in adults (p < 0.05). In vitro findings were further confirmed by in vivo experiments.