nitrophenols and Anemia--Aplastic

Using genetically modified mouse models, we report here that p53 upregulated modulator of apoptosis (Puma) and Bcl-2 interacting mediator of cell death (Bim), two pro-apoptotic members of the B-cell lymphoma protein-2 (Bcl-2) family of proteins, cooperate in causing bone marrow and gastrointestinal tract toxicity in response to chemo and radiation therapy. Deletion of both Puma and Bim provides long-term survival without evidence of increased tumor susceptibility following a lethal challenge of carboplatin and ionizing radiation. Consistent with these in vivo findings, studies of primary mast cells demonstrated that the loss of Puma and Bim confers complete protection from cytokine starvation and DNA damage, similar to that observed for Bax/Bak double knockout cells. Biochemical analyses demonstrated an essential role for either Puma or Bim to activate Bax, thereby leading to mitochondrial outer membrane permeability, cytochrome c release and apoptosis. Treatment of cytokine-deprived cells with ABT-737, a BH3 mimetic, demonstrated that Puma is sufficient to activate Bax even in the absence of all other known direct activators, including Bim, Bid and p53. Collectively, our results identify Puma and Bim as key mediators of DNA damage-induced bone marrow failure and provide mechanistic insight into how BH3-only proteins trigger cell death.

Topics: Anemia, Aplastic; Animals; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Bcl-2-Like Protein 11; Biphenyl Compounds; Bone Marrow Diseases; Bone Marrow Failure Disorders; Cell Survival; Cytochromes c; DNA Damage; Gene Deletion; Hemoglobinuria, Paroxysmal; Mast Cells; Membrane Proteins; Mice; Mice, Knockout; Mitochondrial Membranes; Nitrophenols; Permeability; Piperazines; Proto-Oncogene Proteins; Sulfonamides; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

The hepatic ultrastructural aspect and the hepatic bilirubin (Bil-GT) and paranitrophenol (PNP-GT) glucuronyl transferase activities were studied in twenty subjects with a chronic hemolytic anemia (HA) and five subjects with an aplastic anemia. In chronic HA: the hepatic ultrastructural aspect showed mitochondrial abnormalities affecting structure (paracrystalline inclusions), size (giant mitochondria) and shape (irregular mitochondria); there was a decrease of Bil-GT activity in 80 percent of the patients. No connection could be shown between the HA etiology and the degree of the enzymatic activity decrease. The physiopathological mechanism of this enzymatic activity decrease is unknown; no deficiency of PNP-GT was observed; in chronic aplastic anemias there does not seem to be any modification, either of Bil-GT activity, or of hepatic PNP-GT activity. It is concluded that Bil-GT is often decreased in HA and that neither Bil-GT measurement nor the ultrastructural aspect of the liver distinguish chronic HA from Gilbert's syndrome.

Topics: Anemia, Aplastic; Anemia, Hemolytic; Bilirubin; Glucuronates; Hexosyltransferases; Humans; Liver; Mitochondria, Liver; Nitrophenols