Induction of Hepatic δ-Aminolevulinic Acid Synthetase Activity in Strains of Inbred Mice

Abstract

Abstract δ-Aminolevulinic acid synthetase activity is increased in hepatic homogenates from mice that have been fasted or treated (or both) with 3,5-dicarbethoxy-1,4-dihydro-2,4,6-trimethylpyridine (DDC). Comparison of δ-aminolevulinic acid synthetase activity in livers from adult female mice of 15 inbred strains showed significant differences (p l 0.01) among the strains in the amount of enzyme activity normally present and in the amount present after induction. After DDC administration, δ-aminolevulinic acid synthetase activity increased at a linear rate for 12 hours and then reached a plateau at a level that was maintained until at least 20 hours after drug administration. Strain differences were maintained over a range of DDC doses from 28 mg per kg to 500 mg per kg (the highest dose tested). No significant differences in plasma DDC levels were noted between strains of and induced activity. Representative strains with high and low DDC-induced enzyme activity were compared in detail. Neither modification of the glycine, pyridoxal 5'-phosphate, or EDTA concentrations nor substitution of other buffers for the usual Tris buffer changed the relative enzyme activities of homogenates. Addition of succinyl coenzyme A or a succinyl CoA generating system increased total homogenate activity to the same extent in high and low strains. In animals from both classes, added succinate inhibited δ-aminolevulinate production. When hepatic homogenates of DDC-treated mice were fractionated by differential centrifugation, no substantial differences were noted among strains in the subcellular distribution of δ-aminolevulinic acid synthetase activity. Our data suggest that among inbred strains of mice there are either differences in the number of δ-aminolevulinic acid synthetase enzyme molecules present or differences in the catalytic activity of a structurally modified enzyme produced in response to fasting or DDC administration (or both) and that genetic factors are responsible for this heterogeneity of response.