Acatalasia

Abstract: Pathogenic microorganisms possess antioxidant defense mechanisms for protection from reactive oxygen metabolites such as hydrogen peroxide (H2O2), which are generated during the respiratory burst of phagocytic cells. These defense mechanisms include enzymes such as catalase, which detoxify reactive oxygen species, and DNA repair systems which repair damage resulting from oxidative stress. To determine the relative importance of these two potentially protective defense mechanisms against oxidative stress encountered by Salmonella during infection of the host, a Salmonella typhimurium double mutant unable to produce either the HPI or HPII catalase was constructed, and compared with an isogenic recA mutant deficient in DNA repair. The recA mutant was hypersusceptible to H2O2 at low cell densities in vitro, while the catalase mutant was more susceptible to high H2O2 concentrations at high cell densities. The catalase mutant was found to be resistant to macrophages and retained full murine virulence, in contrast to the recA mutant which previously was shown to be macrophage-sensitive and attenuated in mice. These observations suggest that Salmonella is subjected to low concentrations of H2O2 while at relatively low cell density during infection, conditions requiring an intact DNA repair system but not functional catalase activity.

Abstract: Activated oxygen species have been demonstrated to be the important agents in oxygen toxicity by disrupting the structural and functional integrity of cells through lipid peroxidation events, DNA damage and protein inactivation. The biological consequences of free radical damage have long been hypothesized to be a causal agent in many aging-related diseases. Catalase (H2O2:H2O2 oxidoreductase; EC 1.15.1.1) is one of several enzymes involved in the scavenging of oxygen free radicals and free radical derivatives. The structural gene for catalase in Drosophila melanogaster has been localized to region 75D1-76A on chromosome 3L by dosage responses to segmental aneuploidy. This study reports the isolation of a stable deficiency, Df(3L)CatDH104(75C1-2;75F1), that uncovers the catalase locus and the subsequent isolation of six acatalasemic mutants. All catalase mutants are viable under standard culture conditions and recessive lethal mutations within the 75Cl-F1 interval have been shown not to affect catalase activity. Two catalase mutations are amorphic while four are hypomorphic alleles of the Cat+ locus. The lack of intergenic complementation between the six catalase mutations strongly suggests that there is only one functional gene in Drosophila. One acatalesemic mutation was mapped to position 3-47.0 which resides within the catalase dosage sensitive region. While complete loss of catalase activity confers a severe viability effect, residual levels are sufficient to restore viability to wild type levels. These results suggest a threshold effect for viability and offer an explanation for the general lack of phenotypic effects associated with the known mammalian acatalasemics.

Abstract: Rationale: Although reactive oxygen species (ROS) are generally considered to be proinflammatory and to contribute to cellular and organ dysfunction when present in excessive amounts, there is evidence that specific ROS, particularly hydrogen peroxide (H2O2), may have antiinflammatory properties. Objectives: To address the role that increases in intracellular H2O2 may play in acute inflammatory processes, we examined the effects of catalase inhibition or the absence of catalase on LPS-induced inflammatory responses. Methods: Neutrophils from control or acatalasemic mice, or control neutrophils incubated with the catalase inhibitor aminotriazole, were treated with LPS, and levels of reactive oxygen species, proteasomal activity, NF-κB activation, and proinflammatory cytokine expression were measured. Acute lung injury (ALI) was produced by intratracheal injection of LPS into control, acatalasemic-, or aminotriazole-treated mice. Measurements and Main Results: Intracellular levels of H2O2 were increased in acatalasemic neutrophils and in neutrophils exposed to aminotriazole. Compared with LPS-stimulated neutrophils from control mice, neutrophils from acatalasemic mice or neutrophils treated with aminotriazole demonstrated reduced 20S and 26S proteasomal activity, IκB-α degradation, NF-κB nuclear accumulation, and production of the proinflammatory cytokines TNF-α and macrophage inhibitory protein (MIP)-2. The severity of LPS-induced ALI was less in acatalasemic mice and in mice treated with aminotriazole as compared with that found in control mice. Conclusions: These results indicate that H2O2 has antiinflammatory effects on neutrophil activation and inflammatory processes, such as ALI, in which activated neutrophils play a major role.

Abstract: Diabetes is a group of metabolic diseases characterized by hyperglycemia. Clinical expression of diabetes is dependent on both genetic and acquired factors (1). The metabolic effects of oxidants, which are believed to contribute to many diseases, may influence the development of some forms of diabetes. The oxidant hydrogen peroxide (H2O2) is a by-product of normal cellular respiration and is also formed from superoxide anion by the action of superoxide dismutase. H2O2 has been reported to damage pancreatic β-cells (2,3,4) and inhibit insulin signaling (5). The enzyme catalase (E.C. 1.11.1.6) has a predominant role in controlling the concentration of H2O2 (6,7), and consequently, catalase protects pancreatic β-cells from damage by H2O2 (3,8). Low catalase activities, which have been reported in patients with schizophrenia and atherosclerosis (9), are consistent with the hypothesis that long-term oxidative stress may contribute to the development of a variety of late-onset disorders, such as type 2 diabetes (10,11). Two categories of genetic deficiencies of erythrocyte catalase, which were reviewed in 1995 (12), are acatalasemia (<10% of normal activity) and hypocatalasemia (∼50% of normal activity). In Hungary, 1 acatalasemic and 12 hypocatalasemic families have been described (10,13,14). These families include 2 acatalasemic, 61 hypocatalasemic, and 66 normocatalasemic individuals. Diabetes was diagnosed in eight members of these families. Both acatalasemic individuals were women with type 2 diabetes; five of the hypocatalasemic women had type 2 diabetes, and the only man with diabetes among the eight was hypocatalasemic. Therefore, for this cohort with inherited catalase deficiency, the incidence …