Cyclic Nucleotide Phosphodiesterase Activities of the Human Liver: Comparison between Control and Reye's Syndrome Samples

Abstract

Summary: The specific activity and kinetic constants of the four forms of cyclic nucleotide phosphodiesterase (PDE) activities of liver obtained at autopsy from patients with and without Reye's syndrome have been analyzed and compared. Assays were conducted on supernatants of 30,000 × g spun homogenates after dialysis to remove endogenously accumulated substrate.Km values were derived by the double reciprocal plot method. A higher mean value for the low affinity cAMP activity is found in Reye's subjects (11.36 ± 7.33 × 10-4 M compared to 3.6 ± 1.73 × 10-4 M for controls). Values for the other forms are similar between groups. Values for controls are: 4.03 ± 1.8 × 10-6 M for the high affinity cAMP PDE activity and 2.57 ± 0.27 × 10-4 M and 8.28 ± 5.74 × 10-8 M for the low plus high affinity cGMP PDE activities. Differences in Vmax values are not statistically significant.At 10 and 500 4mUM cAMP concentrations, infants exhibit the highest specific activities. When all subjects in each group are included in calculation of the mean specific activity, no difference of significance is apparent. If all infant values are excluded from both groups, the mean specific activity of the high Km or low affinity cAMP PDE obtained for Reye's subjects is significantly higher than for control subjects (4.18 ± 2.17 nmol/mg/min compared to 1.52 ± 0.93). Such differences are not observed for the low Km or high affinity cAMP PDE or for the high and low affinity cGMP PDE enzymes.In supernatant fractions from both groups, the presence of 10-6 M cGMP enhanced the cAMP hydrolyzing capacity. Higher concentrations of cGMP are inhibitory for both forms of cAMP PDE.Speculation: These observations raise the distinct possibility that children who develop Reye's syndrome may exhibit an altered responsiveness to the polypeptide hormones which utilize the second messenger system to produce their intracellular effects.