Embryonic catalase protects against endogenous and phenytoin-enhanced DNA oxidation and embryopathies in acatalasemic and human catalase-expressing mice.
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The genetics of catalase in Drosophila melanogaster: isolation and characterization of acatalasemic mutants.
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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. (+info)
Multiple peroxisomal enzymatic deficiency disorders. A comparative biochemical and morphologic study of Zellweger cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy.
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Biologic, morphologic, and biochemical investigations performed in 2 patients demonstrate multiple peroxisomal deficiencies in the cerebrohepatorenal syndrome of Zellweger (CHRS) and neonatal adrenoleukodystrophy (NALD). Very long chain fatty acids, abnormal bile acids, including bile acid precursors (di- and trihydroxycoprostanoic acids), and C29-dicarboxylic acid accumulated in plasma in both patients. Generalized hyperaminoaciduria was also present. Peroxisomes could not be detected in CHRS liver and kidney; however, in the NALD patient, small and sparse cytoplasmic bodies resembling altered peroxisomes were found in hepatocytes. Hepatocellular and Kupffer cell lysosomes were engorged with ferritin and contained clefts and trilaminar structures believed to represent very long chain fatty acids. Enzymatic deficiencies reflected the peroxisomal defects. Hepatic glycolate oxidase and palmitoyl-CoA oxidase activities were deficient. No particle-bound catalase was found in cultured fibroblasts, and ether glycerolipid (plasmalogen) biosynthesis was markedly reduced. Administration of phenobarbital and clofibrate, an agent that induces peroxisomal proliferation and enzymatic activities, to the NALD patient did not bring about any changes in plasma metabolites, liver peroxisome population, or oxidizing activities. (+info)
Deficiency in the catalase activity of xeroderma pigmentosum cell and simian virus 40-transformed human cell extracts.
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It has been previously shown that skin biopsies isolated from various xeroderma pigmentosum (XP) patients present a permanent decline in catalase activity from the onset of the disease to the tumor formation. We report here that cultured XP cell strains are also markedly deficient in the catalase activity with about only 25% of the activity measured in normal human cells. No direct correlation between catalatic activity and excision repair ability has been found, since a XP variant line is as deficient as an XP-C strain. The exact cause of the catalase deficiency is still unknown but could be due to the synthesis of a modified enzyme or to an abnormal regulation leading to a limited enzyme synthesis. Furthermore, simian virus 40 transformation of normal and radiosensitive cells (XP, ataxia telangiectasia) provokes a decrease in catalase activity of about 80% compared to the control derivatives. Mathematical analysis performed on our data shows a clearcut distinction between XP and normal cells while some of the XP heterozygote cells exhibit an intermediate behavior. Although most of the XP syndrome could be explained by the impairment in the excision repair ability, the decrease in catalase activity leading to a probable increase in intracellular H2O2 concentration and/or to a higher sensitivity to any oxygen-activated species could represent an additive effect in inducing the carcinogenic process. (+info)
Isolation of a cDNA clone for murine catalase and analysis of an acatalasemic mutant.
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We have investigated the genetic control of murine catalase expression by analyzing catalase transcription and translation products from the tissues of control (Csa) and acatalasemic (Csb) mouse strains. Csb animals possess nearly normal catalase enzyme activity levels in liver, while displaying approximately 20 and 1% of normal activity levels in kidney and red blood cells, respectively. Immunoblot analyses of catalase in these tissues have revealed reduced levels of immunologically reactive catalase protein in Csb kidney and red blood cells, paralleling the reduction of catalase enzyme activity in these tissues. In order to determine the molecular basis for Csb acatalasemia, we have isolated a cDNA clone for murine catalase and have used this probe to analyze Csa and Csb genomic DNA and catalase mRNA. These studies have revealed: 1) no restriction fragment length polymorphisms between Csa and Csb genomic DNAs; 2) no differences in the levels of Csa and Csb catalase mRNA within a single tissue; and 3) no differences in the sizes of Csa and Csb catalase mRNAs. These observations suggest that the genetic defect that produces the tissue-specific reduction of catalase expression in Csb mice is not due to a marked rearrangement of DNA within the Csb catalase structural gene. Furthermore, the Csb mutation does not act at the level of gene transcription or mRNA stability, but rather at the level of mRNA translation and/or catalase protein turnover. (+info)