dinoprost and Lymphoma

Apurinic/apyrimidinic endonuclease is a key enzyme in the process of base excision repair, required for the repair of spontaneous base damage that arises as a result of oxidative damage to DNA. In mice, this endonuclease is coded by the Apex gene, disruption of which is incompatible with embryonic life. Here we confirm the embryonic lethality of Apex-null mice and report the phenotypic characterization of mice that are heterozygous mutants for the Apex gene (Apex+/-). We show that Apex heterozygous mutant cells and animals are abnormally sensitive to increased oxidative stress. Additionally, such animals manifest elevated levels of oxidative stress markers in serum, and we show that dietary supplementation with antioxidants restores these to normal levels. Apex+/- embryos and pups manifest reduced survival that can also be partially rescued by dietary supplementation with antioxidants. These results are consistent with a proposed role for this enzyme in protection against the deleterious effects of oxidative stress and raise the possibility that humans with heterozygous mutations in the homologous HAP1 gene may be at increased risk for the phenotypic consequences of oxidative stress in cells.

Topics: Adenocarcinoma, Papillary; Animals; Ascorbic Acid; Carbon-Oxygen Lyases; Cell Survival; Cells, Cultured; Dietary Supplements; Dinoprost; DNA-(Apurinic or Apyrimidinic Site) Lyase; Dose-Response Relationship, Drug; Embryo, Mammalian; Female; Fibroblasts; Genotype; Heterozygote; Lipid Peroxides; Lung Neoplasms; Lymphoma; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Mutant Strains; Oxidative Stress; Paraquat; Phenotype; Vitamin E; Vitamin K

The effect of prolactin on phospholipid metabolism in the prolactin-dependent rat lymphoma cell line Nb2 was investigated in cells prelabeled with [3H]arachidonic acid or [3H]ethanolamine. Prolactin (20 ng/ml) caused (a) a 20-60% loss of radiolabeled phosphatidylethanolamine within 0.5 to 2 min, (b) a loss of [3H]ethanolamine-labeled phosphatidylethanolamine from crude membranes, (c) a rapid accumulation of [3H]phosphoethanolamine and [3H]ethanolamine, and (d) a transient increase (15 s to 2 min) in prostaglandin F2 alpha and E2. Arachidonic acid (1-2 micrograms/ml) induced Nb2 cell growth but prostaglandin F2 alpha, E2, ethanolamine, and phosphoethanolamine did not. Prostaglandin E2 inhibited while prostaglandin F2 alpha enhanced growth in the presence of prolactin or arachidonic acid. These results suggest that stimulation of Nb2 cell growth by prolactin is linked to activation of a phosphatidylethanolamine-specific phospholipase C. Arachidonic acid and prostaglandin F2 alpha may participate in regulating the mitogenic action of prolactin.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cell Division; Dinoprost; Dinoprostone; Lymphoma; Phosphatidylethanolamines; Prolactin; Rats; Receptors, Prolactin; Tumor Cells, Cultured