1988: Clastogenic factor in ischemia-reperfusion injury during open-heart surgery: protective effect of allopurinol. Updated in 1995.
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Allopurinol↗
Biomedical subjects
I Emerit
Publications and source records attributed to I Emerit.
Radiation-induced clastogenic factors: anticlastogenic effect of Ginkgo biloba extract.
Clastogenic factors (CFs) were first described in the blood of persons irradiated accidentally or for therapeutic reasons. Work of our laboratory has shown that they occur also under other circumstances, which are characterized by oxidative stress, and that CF-induced chromosome damage is regularly prevented by superoxide dismutase (SOD). Recently we found CFs in a high percentage of salvage personnel of the Chernobyl reactor accident. These liquidators represent a high-risk population and might benefit from cancer chemoprevention by antioxidants. SOD would have to be injected and is not appropriate for long-term prophylactic treatment. In the present study, we therefore evaluated the anticlastogenic effect of the Ginkgo biloba extract EGb 761, which is known for its superoxide scavenging properties. EGb 761 was tested on CF-treated blood cultures of healthy donors. After establishing the optimal protective EGb concentration, using CFs produced by irradiation of whole blood from healthy volunteers, the extract was tested on cultures exposed to CFs from plasma of persons irradiated as liquidators. The anticlastogenic effect could be confirmed for a final concentration of 100 micrograms/ml. In 12 consecutive experiments, CFs induced an average of 18.00 +/- 4.41 aberrations/100 cells. This was reduced to 7.33 +/- 3.08 in the parallel cultures receiving 100 micrograms/ml EGb 761 (p < .001). SOD was anticlastogenic in the same system at concentrations of 30 cytochrome C units/ml (approximately 10 micrograms/ml). Preliminary results obtained in a small series of liquidators showed regression or complete disappearance of CFs in the plasma after 2 months of treatment with EGb 761 (3 x 40 mg/d).
Antimutagenic Agents↗
Plasma from patients exposed to ischemia reperfusion contains clastogenic factors and stimulates the chemiluminescence response of normal leukocytes.
Clastogenic factors (CFs) are released by cells exposed to superoxide radicals and are found in various situations of oxidative stress. Certain of their components stimulate further superoxide production by competent cells, as shown with cytochrome c assay in previous work. In the present study, we report CF formation after ischemia reperfusion in patients undergoing coronary bypass surgery. Plasma ultrafiltrates, collected 20 min after reperfusion, had clastogenic properties in contrast to those collected before ischemia. We also show that the luminol-enhanced chemiluminescence response of neutrophils from healthy persons is increased when these cells are exposed to CF-containing postreperfusion samples from patients. Light emission was reduced to control values in the presence of superoxide dismutase. The burst of oxyradicals upon reperfusion is probably the initiating event of CF formation, which in turn leads to further oxyradical generation. This amplification process may explain why detectable levels of CF need a delay of at least 10 min. The activated state of neutrophils in ischemia reperfusion is at once a consequence and a source of CFs. Individual variation in the persistence of this clastogenic and leukocyte-activating material was observed. Therefore, antioxidants for prevention of ischemia reperfusion injury should be continued during the postoperative course.
Antioxidants↗
Clastogenic factors in plasma of HIV-1 infected patients.
The objective of this study was to investigate the clastogenic activity of plasma ultrafiltrates from HIV-1 infected patients. Clastogenic factors are chromosome-damaging agents with low molecular weight (< 10,000 daltons) which cause chromosome aberrations, sister chromatid exchanges, DNA strand breakage, and gene mutation. They have first been described in the plasma of irradiated persons, but they are also found in hereditary breakage syndromes and chronic inflammatory diseases with autoimmune reactions. Their formation and their clastogenic effects are modulated by superoxide anion radicals. We analyzed a total of 22 HIV-1 positive patients in comparison to 20 reference plasma samples from healthy HIV negative blood donors of similar age. The plasma ultrafiltrates (filter cutoff 10,000 daltons) from patients induced a statistically significant increase in chromosomal breakage in the cytogenetic test system (20.5 +/- 6.8 aberrations per 100 cells), while no increase was observed in test cultures exposed to plasma ultrafiltrates from healthy blood donors (6.3 +/- 2.9 aberrations per 100 cells). The breakage values were slightly, but not significantly, lower in the 10 patients with more than 200 T-helper cells/ml (18 +/- 4 aberrations per 100 cells), than in the 12 patients with less than 200 T-helper cells/ml (22.3 +/- 7.9 aberrations per 100 cells). HIV patients with high clastogenic activity (induction of more than 20 aberrations per 100 cells, range 20 to 39) showed higher plasma levels for malondialdehyde than those with lower clastogenic activity (less than 20 aberrations per 100 cells, range 12 to 18). However, the difference was statistically not significant. Another lipid peroxidation product, 4-hydroxynonenal, was increased equally in both groups. There were no significant differences in water- and lipid-soluble plasma antioxidants between the low- and high-breakage group. In agreement with previous findings, the clastogenic effects of plasma ultrafiltrates in the test cultures were reduced by the antioxidant enzyme superoxide dismutase. The presence of clastogenic factors in the plasma of HIV patients is further evidence for a prooxidant state in these persons. Since clastogenic factor formation appears to occur at an early stage of the disease, it may be significant for virus release or activation, because of the superoxide anion stimulating effects of clastogenic factors. From a practical standpoint, clastogenic factors may be useful for evaluation of promising drugs.
Acquired Immunodeficiency Syndrome↗
Adenosine deaminase in progressive systemic sclerosis.
The aim of the present study was to confirm the increase of adenosine deaminase (ADA) activity in progressive systemic sclerosis (PSS), described by Sasaki & Nakajima, and to compare plasma ADA activity of patients in different stages of the disease. Enzyme activity was measured with a colorimetric assay. The 48 patients were subdivided into 3 groups: subgroup 1 (n = 10), disease still limited to the skin; subgroup 2 (n = 21), involvement of the skin and oesophagus; and subgroup 3 (n= 17), involvement of the skin and multiple internal organs. ADA levels were highest in subgroup 3. However, the difference with respect to subgroup 2 did not reach statistical significance. Subgroup 1 was different from controls and subgroups 2 and 3 (p<0.001). Our results confirm that ADA activity is increased in PSS, and that this finding is observed even in the early stages of the disease process. We speculate that the increase in ADA, a well-known marker of T-cell activation, might be an indicator of disease activity in PSS, in the beginning as well as during phases of exacerbation in later stages of the disease.
Adenosine Deaminase↗
Clastogenic factors in the plasma of Chernobyl accident recovery workers: anticlastogenic effect of Ginkgo biloba extract.
Clastogenic factors are found in the plasma of persons irradiated accidentally or therapeutically. They persisted in the plasma of A-bomb survivors over 30 years. Clastogenic factors were found in 33 of 47 Chernobyl accident recovery workers (often referred to as liquidators) in a previous study (I. Emerit et al., J. Cancer Res. Clin. Oncol. 120, 558-561, 1994). In the present study, we show that there is a positive correlation between clastogenic activity and dose and that these biomarkers of oxidative stress can be influenced successfully by appropriate antioxidant treatment. With the authorization of the Armenian Ministry of Health, 30 workers were treated with antioxidants from Ginkgo biloba leaves. The extract EGb 761 containing flavonoids and terpenoids was given at a daily dose of 3 x 40 mg (Tanakan, IPSEN, France) during 2 months. The clastogenic activity of the plasma was reduced to control levels on the first day after the end of the treatment. A 1-year follow-up showed that the benefit of the treatment persisted for at least 7 months. One-third of the workers again had clastogenic factors after 1 year, demonstrating that the process which produced clastogenic factors continued. However, the observation that antioxidants do not have to be given continuously is encouraging for intervention trials on a large-scale basis. These appear justified, since clastogenic factors are thought to be risk factors for the development of late effects of irradiation.
Adult↗
Chromosome damage in PUVA-treated human lymphocytes is related to active oxygen species and clastogenic factors.
Besides the direct interaction of psoralens with DNA and other macromolecules, the role of reactive oxygen species in the PUVA-induced cellular injury has been stressed. The present study shows that treatment of human blood cultures with 5-methoxypsoralen or 8-methoxypsoralen, followed by UVA exposure, results in chromosome damage. The supernatant of these cultures contains secondarily formed chromosome damaging material, called clastogenic factor (CFs). Not only CF formation, but also CF action is inhibited by superoxide dismutase (SOD), suggesting that superoxide is formed on the pathway to chromosome aberration. CF is detectable in the cell culture supernatants after a minimal delay of 18 h, and reaches a plateau at 24 h of cultivation. SOD is no longer protective if added after 24 h, i.e., the enzyme can prevent, but not repair the oxyradical-induced damage.
5-Methoxypsoralen↗
Transferable clastogenic activity in plasma from persons exposed as salvage personnel of the Chernobyl reactor.
Clastogenic factors were first described in the plasma of people who had been accidentally or therapeutically irradiated. They were found also in A-bomb survivors, where they persisted for many years after the irradiation. The present study searched for these factors in the plasma of 32 civil workers from Armenia, who had been engaged as "liquidators" around the Chernobyl atomic power station in 1986. It also included 15 liquidators who had emigrated from the ex-Soviet Union to Israel. Reference plasma samples were obtained from 41 blood donors from the Armenian Blood Center in Yerevan. The samples were tested for their clastogenic activity in blood cultures from healthy donors. The majority of results from the liquidators exceeded those from the unexposed reference samples. The samples from the first Armenian group, with the higher average irradiation dose (0.6 +/- 0.6 Gy), were more clastogenic than those from the second group exposed to 0.2 +/- 0.2 Gy. The number of aberrations in the test cultures was 17.9 +/- 2.9% and 10.5 +/- 3.8% respectively, compared to 5.7 +/- 3.2% in the cultures exposed to the reference ultrafiltrates from Armenian blood donors. The samples from the Israeli liquidators also induced significantly increased aberration rates (14.0 +/- 3.9% aberrant cells). The clastogenic activity was regularly inhibited by superoxide dismutase, indicating that the chromosome-damaging effects of radiation-induced clastogenic factors are exerted via the intermediation of superoxide radicals, as is known for clastogenic factors of different origin.
Accidents↗
Reactive oxygen species, chromosome mutation, and cancer: possible role of clastogenic factors in carcinogenesis.
Superoxide radicals may induce genotoxic effects by indirect action mechanisms, implicating the formation of more long-lived, secondary clastogenic material called chromosome breakage factors or clastogenic factors (CF). CF are produced via the intermediacy of superoxide, and stimulate further superoxide production by competent cells. This results in a selfsustaining and longlasting process of clastogenesis, which may exceed the DNA repair system and ultimately lead to cancer. An increased cancer risk is indeed observed in conditions accompanied by CF formation. These include irradiated persons, asbestos workers, patients with chronic inflammatory diseases, HIV-infected persons, and the congenital breakage syndromes ataxia telangiectasia, Bloom's syndrome, and Fanconi's anemia. Because reactive oxygen species (ROS) are implicated in CF formation and CF action, antioxidants may be protective as anticlastogens and consequently as anticarcinogens. In persons at high risk because of their occupation, life style or place of residence, the presence of CF may represent an indication for chemoprevention of cancer by antioxidants. CF can be useful as biochemical markers and intermediate endpoints for the evaluation of promising drugs. They are therefore not only of interest as a mechanism by which ROS may exert genotoxic effects, but also have practical implications.
Animals↗
Oxyradical-mediated chromosome damage in patients with familial Mediterranean fever.
Increased chromosome breakage is observed in patients with familial mediterranean fever (FMF). Their plasma contains clastogenic material inducing chromosome damage in cells from healthy persons. It is proposed that increased oxyradical generation by activated polymorphonuclear cells in blood and serosal fluids of these patients leads to the formation of a clastogenic factor (CF), as it is observed in other chronic inflammatory diseases. Also similar to these diseases, the clastogenic effects are prevented by superoxide dismutase and partially by inhibitors of arachidonic acid metabolism.
Adolescent↗
Chromosomal aberrations and neutrophil activation induced by reperfusion in the ischaemic human heart.
Imperfect myocardial protection during prolonged ischaemia results in adverse changes during reperfusion. Clinical studies carried out during cardiac surgery show that: (1) Oxygen free radicals produced during reperfusion can lead to chromosomal damage in leukocytes. However, this effect seems to be prevented by the addition of allopurinol in the cardioplegic solution. (2) Polymorphonuclear leukocytes are directly implicated in situ in the genesis of free radicals responsible for reperfusion injury. (3) Pre-treatment with trimetazidine, an anti-ischaemic drug with antioxidant properties, and addition of the drug to the cardioplegic solution reduced oxygen free radical damage, as shown by a reduced release of malondialdehyde increase and of myosin; moreover, pre-treatment with trimetazidine enabled patients to undergo surgery with improved left ventricular function.
Allopurinol↗
Active oxygen species, articular inflammation and cartilage damage.
Rheumatoid arthritis and osteoarthritis are age-related diseases, in which degenerative changes (arthrosis) and superimposed inflammatory reactions (arthritis) lead to progressive destruction of the joints. Active oxygen species derived from various sources play a role in this process, which may be influenced by appropriate treatment with antioxidants and free radical scavengers.
Aging↗
Free radicals and aging of the skin.
Cutaneous aging is the result of genetically determined or intrinsic aging superimposed by degenerative changes due to actinic irradiation, also called photoaging. The manifestations of cutaneous aging, as it relates to the perception of age, is caused by ultraviolet light, in particular in those parts of the body exposed daily to solar radiation. Free radical generation in the skin by UV light and from other sources, such as cellular infiltrations or the xanthine oxidase reaction, may be detected by direct and indirect methods. The decrease in antioxidant enzymes and small molecular weight antioxidants such as glutathione, vitamin E and ubiquinone upon exposure to UV light is an indication that the pro-antioxidant balance can be overwhelmed by acute or chronic photo-oxidative stress. Antioxidant supplementation is therefore a means for prevention or at least retardation of premature cutaneous aging.
Animals↗
Formation of a clastogenic factor by asbestos-treated rat pleural mesothelial cells.
The data of the present study indicate that chrysotile induces the formation of a clastogenic factor (CF) when mesothelial cells are exposed to these fibers in vitro. Ultrafiltrates of culture media induce chromosome damage in human lymphocytes used as a test system for the detection of clastogenic activity in conditioned media. According to the cut off of the filters (10,000 dalton), CF is a small molecule. Its exact nature is unknown. The intermediacy of active oxygen species in CF formation is suggested by the anticlastogenic effect of antioxidant enzymes such as superoxide dismutase and catalase. The data are similar to those obtained with other membrane-active agents, in particular the tumor promoter tetra-decanoylphorbol acetate (TPA). The model of membrane-mediated chromosome damage with CF formation is proposed for asbestos-induced cell injury.
Animals↗
Hydroxynonenal, a component of clastogenic factors?
Exposure of human lymphocyte cultures to superoxide generated by the xanthine-xanthine oxidase (X-XO) system, resulted in formation of a clastogenic factor (CF), as expected from previous work. We speculated that arachidonic acid (AA), the major polyunsaturated fatty acid of biological membranes, was oxidized via the cyclooxygenase-lipoxygenase pathways or nonenzymatically by oxygen free radicals in the culture medium to products with clastogenic properties. In the present study, we analyzed CF for AA-derived products and tested corresponding commercial standards for their clastogenic properties. The results show that prostaglandins, thromboxane, and H(P)ETEs were not increased in supernatants from X-XO treated cultures compared to untreated cultures. Synthetic H(P)ETEs added to the medium of lymphocyte cultures were only slightly or not clastogenic. In contrast hereto, the degradation product 4-hydroxynonenal was found in 50% of CF samples, while it was absent in all 43 control samples. The kinetics of detectability in the culture medium was similar to that of CF. Also, the clastogenic effect of synthetic 4-hydroxynonenal at concentrations as low as 0.1 microM suggested that this aldehyde, known for its genotoxic effects, was a clastogenic component of CF. The indirect action mechanisms of 4-hydroxynonenal via inactivation of functional SH groups in DNA polymerases, may explain why chromatid-type damage is predominant in lymphocytes exposed to CF in the Go-G1 phase of the cell cycle. This particularly was already stressed 20 years ago in the first observations of radiation-induced CF. However, 4-hydroxynonenal is not the only clastogenic component of CF.(ABSTRACT TRUNCATED AT 250 WORDS)
Aldehydes↗
Allopurinol in ischemia--reperfusion injury of heart.
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Allopurinol↗
Clastogenic inosine nucleotide as components of the chromosome breakage factor in scleroderma patients.
In the present study, we attempted to identify the chemical nature of the clastogenic factor (CF) from patients with progressive systemic sclerosis (scleroderma). Computerized mass spectrometry of clastogenic fractions obtained by HPLC of plasma ultrafiltrates detected molecular peaks compatible with inosine triphosphate and inosine diphosphate (ITP and IDP). The concomitant detection of IDP, together with ITP, and the absence of these peaks in nonclastogenic fractions and corresponding control fractions are arguments in favor of a biological relevance of these observations. The most important confirmation came from the clastogenic effect of commercial ITP and IDP added to the culture medium of the test cultures. The induction of chromatid type damage by these substances in lymphocytes exposed in the G0 phase of their cell cycle and the prevention of this damage by superoxide dismutase are analogous to the observations with CF.
Cells, Cultured↗
Clastogenic factors: detection and assay.
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Animals↗