Release of active oxygen radicals by leukocytes of Fanconi anemia patients

Abstract

The release of oxygen radicals by blood and bone marrow leukocytes of patients with Fanconi anemia (FA) has been studied. It was found that the nonstimulated FA leukocytes and those stimulated by concanavalin A, SiO2, latex, and opsonized zymosan produced enhanced levels of luminol- and lucigenin-dependent chemiluminescence (CL) in comparison with normal leukocytes. At the same time, the ratio of the intensity of lucigenin-dependent CL to that of luminol-dependent CL was significantly smaller for FA leukocytes than for normal leukocytes. From these findings and from the effects of antioxidative enzymes and free radical scavengers on CL, it was concluded that FA leukocytes release enhanced amounts of oxygen radicals and that these free radicals contain enhanced amounts of hydroxyl or hydroxyl-like radicals more active than superoxide ion. It was proposed that elevated reactivity of the oxygen radicals released by FA leukocytes may be a major factor in the development of Fanconi anemia; this proposal is supported by the first positive results of treatment of FA patients with rutin (a nontoxic natural free radical scavenger and chelator).

Defective hematopoiesis and hepatic steatosis in mice with combined deficiencies of the genes encoding Fancc and Cu/Zn superoxide dismutase

“…Increased superoxide production by Fancc Ϫ/Ϫ Sod1 Ϫ/Ϫ liver cell cultures was interesting given the reports of elevated ROS generation by FA cells, 21,22 and the reported protective effects of SOD, where extrinsic SOD reduced the high rates of chromosomal breakage in FA cells, and also diminished MMC cytotoxicity. 16,42,43 Interestingly, reduced SOD1 levels have been reported in FA erythrocytes.…”

“…[18][19][20] Increased production of ROS by FA cells, such as leukocytes and fibroblasts, has also been reported, suggesting that FANCC might regulate the generation of these species. 21,22 A potential endogenous source of superoxide, the NADPH cytochrome P-450 reductase (RED) system, has also been implicated in FA. Not only were chromosomal breaks in FA cells reduced by cytochrome P-450 inhibition, but evidence of a direct physical interaction between FANCC and RED was reported, 23,24 leading to the hypothesis that FANCC might protect cells from ROS via regulation of RED activity.…”

Oxidative stress in Fanconi anaemia: from cells and molecules towards prospects in clinical management

“…Exposure of FA lymphoblastoid cells to hydrogen peroxide resulted in excess oxidative damage both of DNA and RNA (Takeuchi and Morimoto , 1993 ) that was suggested to relate to a catalase defi ciency. Excess luminol-dependent chemiluminescence (LDCL), a direct end point of reactive oxygen species (ROS) formation, was found in freshly drawn leucocytes from FA patients and, to a lesser yet signifi cant extent, in FA heterozygotes (Korkina et al , 1992 ).…”

“…In the same three decades, a number of independent investigations provided in vivo, in vitro , and molecular evidence pointing to major roles of OS in FA phenotype (Schindler and Hoehn , 1988 ;Korkina et al , 1992 ;Takeuchi and Morimoto , 1993 ;Schultz and Shahidi , 1994 ;Degan et al , 1995 ;Pagano et al , 2004 ), as well as in the functions of some FANC proteins (Kruyt et al , 1998 ;Cumming et al , 2001 ;Futaki et al , 2002 ;Reuter et al , 2003 ;Park et al , 2004 ;Zanier et al , 2004 ;Du et al , 2008 ;Rani et al, 2008), with direct implications of some FANC proteins in mitochondrial machinery (Bogliolo et al , 2002 ;Rousset et al , 2002 ;Mukhopadhyay et al , 2006 ).…”

Overexpressed thioredoxin compensates Fanconi anemia related chromosomal instability

“…Interestingly, the amount of antioxidative enzymes like catalase, superoxide dismutase, glutathione peroxidase, and phospholipid hydroperoxide glutathione peroxidase are normal in FA ®broblasts (Gille et al, 1987;Ruppitsch et al, 1997). Nevertheless, the intracellular content of reactive oxygen intermediates is elevated (Korkina et al, 1992).…”