Biomedical subjects

M Athar

Publications and source records attributed to M Athar.

At least 19 recordsLinked to original sources

PubMed2003

Host-pathogen interactions during apoptosis.

Host pathogen interaction results in a variety of responses, which include phagocytosis of the pathogen, release of cytokines, secretion of toxins, as well as production of reactive oxygen species (ROS). Recent studies have shown that many pathogens exert control on the processes that regulate apoptosis in the host. The induction of apoptosis upon infection results from a complex interaction of parasite proteins with cellular host proteins. Abrogation of host cell apoptosis is often beneficial for the pathogen and results in a successful host invasion. However, in some cases, it has been shown that induction of apoptosis in the infected cells significantly imparts protection to the host from the pathogen. There is a strong correlation between apoptosis and the host protein translation machinery: the pathogen makes all possible efforts to modify this process so as to inhibit cell suicide and ensure that it can survive and, in some cases, establish latent infection. This review discusses the significance of various pathways/steps during virus-mediated modulation of host cell apoptosis.

Animals↗

PubMed2002

Low iron state is associated with reduced tumor promotion in a two-stage mouse skin carcinogenesis model.

The purpose of this study was to investigate the effect of low iron state in a two-stage mouse skin carcinogenesis model using 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and benzoyl peroxide (BPO)-promoted cutaneous tumorigenesis. All mice were treated with DMBA. Low iron state was achieved by injection with phenylhydrazine hydrochloride and feeding low iron diet. A low iron state resulted in a decrease in tumor incidence (papillomas and carcinomas) and number of tumors/mouse. Also, the conversion of papillomas to carcinomas was lower in mice on a low iron state. BPO treatment enhanced epidermal lipid peroxidation (LPO) and was accompanied by a depletion in the level of epidermal reduced glutathione (GSH) and decrease in the activities of antioxidant enzymes. BPO treatment also increased ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation into cutaneous DNA. Mice in a low iron state were less susceptible to the effects of BPO treatment, as was apparent from a partial recovery of GSH levels and the activities of antioxidant enzymes, as well as a lower induction in ODC activity, [3H]thymidine incorporation into cutaneous DNA and lesser epidermal LPO. As expected, cutaneous iron levels were lower in mice on a low iron state. Thus, our data show that the tumor-promoting potential of BPO is reduced by low iron state in a two-stage mouse skin carcinogenesis model.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2001

Inhibition of benzo[a]pyrene- and cyclophoshamide-induced mutagenicity by Cinnamomum cassia.

Cinnamomum cassia is used as a flavoring spice with some established medicinal properties. In this study, we evaluated the antimutagenic effect of C. cassia against two mutagens, viz. benzo[a]pyrene (B[a]P) and cyclophosphamide (CP). The antimutagenic properties of C. cassia were examined by the Ames test. In vivo chromosomal aberration (CA) and micronuclei tests were also employed to assess the antimutagenic effect of C. cassia in mice after pretreatment with the extract orally for seven consecutive days. To elucidate the mechanism by which C. cassia exerts its antimutagenic effect, certain key enzymes involved in bioactivation and detoxification processes were also investigated. Changes in liver cytochrome P450 (Cyt P450), glutathione content (GSH), glutathione S-transferase (GST), glutathione reductase (GR), and glutathione peroxidase (GPX) were evaluated in pretreated animals. It was observed in the Ames test, bone marrow chromosomal aberration assay, and micronucleus test that C. cassia exerted significant antimutagenic effects against B[a]P and CP in animals treated with the plant extract. C. cassia pretreatment decreased Cyt P450 content but increased GSH content and the activity of glutathione-dependent antioxidant enzymes, viz. GST, GR, and GPX. The present findings demonstrate that the antimutagenic potential of C. cassia could be attributed to its modulatory effect on the xenobiotic bioactivation and detoxification processes.

Administration, Oral↗

PubMed2001

Induction of oxyradicals by arsenic: implication for mechanism of genotoxicity.

Although arsenic is a well-established human carcinogen, the mechanisms by which it induces cancer remain poorly understood. We previously showed arsenite to be a potent mutagen in human-hamster hybrid (A(L)) cells, and that it induces predominantly multilocus deletions. We show here by confocal scanning microscopy with the fluorescent probe 5',6'-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate that arsenite induces, within 5 min after treatment, a dose-dependent increase of up to 3-fold in intracellular oxyradical production. Concurrent treatment of cells with arsenite and the radical scavenger DMSO reduced the fluorescent intensity to control levels. ESR spectroscopy with 4-hydroxy-2,2,6,6-tetramethyl-1-hydroxypiperidine (TEMPOL-H) as a probe in conjunction with superoxide dismutase and catalase to quench superoxide anions and hydrogen peroxide, respectively, indicates that arsenite increases the levels of superoxide-driven hydroxyl radicals in these cells. Furthermore, reducing the intracellular levels of nonprotein sulfhydryls (mainly glutathione) in A(L) cells with buthionine S-R-sulfoximine increases the mutagenic potential of arsenite by more than 5-fold. The data are consistent with our previous results with the radical scavenger DMSO, which reduced the mutagenicity of arsenic in these cells, and provide convincing evidence that reactive oxygen species, particularly hydroxyl radicals, play an important causal role in the genotoxicity of arsenical compounds in mammalian cells.

Animals↗

PubMed2001

Ultraviolet B(UVB)-induced cox-2 expression in murine skin: an immunohistochemical study.

Cyclooxygenase (COX) is the rate-limiting enzyme in the production of prostaglandins from arachidonic acid. This enzyme exists in at least two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays various physiological roles. However, COX-2 expression is induced by a variety of agents, which include pro-inflammatory agents and mitogens. Evidence exists to indicate that increased expression of COX-2 occurs in several types of epithelial neoplasms. In this study, we show the effect of chronic exposure of murine skin to carcinogenic UVB on cutaneous COX-2 expression. SKH-1 mice were irradiated with 180 mJ/cm(2) UVB daily for five days a week for periods ranging from 1 to 20 weeks. Nontumor bearing skin areas of irradiated mice, skin of age-matched controls and benign papillomas and malignant tumors were assessed immunohistochemically for COX-2 expression in these mice. No epidermal staining occurred in any of the non-UVB-treated controls throughout the experiment. Epidermal COX-2 expression only occurred in UVB-irradiated mice. After 1 and 5 weeks of irradiation, patchy epidermal staining mostly confined to the granular layer and stratum corneum was observed. At week 9, staining intensity had increased, particularly in the granular layer. At week 13, staining was uniformly seen in all epidermal layers with particular prominence in the basal cell layer underlying areas of visible epidermal hyperplasia. It is of interest that the most intense staining was seen in the perinuclear region of keratinocytes and at the plasma membrane. At week 20, COX-2 staining was predominant in the granular layer, although in some tissue sections, the entire epidermis was positive. In benign papillomas, staining was confined to the superficial layers of the epidermis and in squamous cell carcinomas (SCCs), patchy staining in the granular and spinous layers predominated. In general, COX-2 expression was more intense in well-differentiated SCCs than in papillomas. In summary, our results indicate that COX-2 serves as an early marker of epidermal UVB exposure and its expression increases in benign papillomas and in SCCs. These results suggest that pharmacological intervention using specific COX-2 inhibitors could have anticarcinogenic effects in UVB-induced human skin cancer.

Animals↗

PubMed2001

Anti-tumor promoting activity of Asteracantha longifolia against experimental hepatocarcinogenesis in rats.

Vegetables, natural products of plant origin and numerous non-nutritive dietary constituents have been shown to play a salutary role in cancer chemoprevention. The present study aims to evaluate the chemopreventive efficacy of the methanol fraction of Asteracantha longifolia seed extract against development of 2-acetylaminofluorene (2-AAF)-selected gamma-glutamyl transpeptidase (gamma-GT)-positive foci following diethylnitrosamine (DEN) initiation. Treatment of rats with doses 200 and 400 mg/kg body weight of methanol extract of A. longifolia seeds on alternate days, subsequent to carcinogen treatment, for 6 weeks significantly reduced the incidence and size distribution of gamma-GT-positive foci and tumor formation. Administration of A. longifolia seeds significantly (P<0.001) ameliorated the activities of antioxidant enzymes, glutathione peroxidase (GPx) and catalase (CAT), in a dose-dependent manner. Prophylactic administration of seed extract simultaneous to 2-AAF in the diet, at same doses, significantly suppressed 2-AAF and partial hepatectomy (PH)-induced ornithine decarboxylase (ODC) activity and [(3)H]thymidine incorporation into hepatic DNA, in a dose-dependent manner. Assimilation of the quantitative foci data together with the findings of the modulation of tumor promoting markers give ample evidence to the anti-tumor promoting potential of A. longifolia seeds against chemically-induced hepatocarcinogenesis in Wistar rats.

2-Acetylaminofluorene↗

PubMed2001

Nitroglycerin: a NO donor inhibits TPA-mediated tumor promotion in murine skin.

Nitroglycerin (GTN), a nitric oxide (NO) generating vasodilator has been used in the present study to assess the role of NO during tumor promotion in murine skin. Administration of GTN to 12-O tetradecanoyl phorbol 13-acetate (TPA)-treated mice resulted in a dose-dependent inhibition in the level of glutathione and the activity of antioxidant enzymes by approximately 16-40% of acetone-treated control. We also observed that GTN application led to a significant reduction in the ornithine decarboxylase (ODC) activity and decreased the rate of [3H]thymidine incorporation into epidermal DNA when compared with the acetone-treated control (P < 0.001). Treatment of DMBA-initiated TPA-promoted mice with GTN increased the latency period, decreased the tumor incidence by 32% and there was a 2-fold decrease in tumor yield (tumor/mouse) as compared with the TPA (alone)-treated group by 20 weeks. From these data, it can be concluded that NO can abrogate the toxic and tumor promoting effects of TPA and GTN can be used as a chemopreventive agent to inhibit tumorigenesis in murine skin.

Animals↗

PubMed2001

Role of iron-dextran on 7,12-dimethylbenz(a) anthracene-initiated and croton oil-promoted cutaneous tumorigenesis in normal and pregnant mice.

Skin chemical carcinogenesis has been divided into the process of initiation, promotion and progression. Earlier, we showed the role of iron overload in the promotion stage of skin carcinogenesis. In this communication, we report that iron overload does not augment croton oil-mediated tumor promotion in 7,12-dimethylbenz(a)anthracene (DMBA)-initiated pregnant mice skin tumorigenesis. Virgin female Swiss mice were given 1 mg iron/mouse/day parenterally for 2 weeks to induce iron overload. After the last injection, a group of mice was left with male mice for 10 days. These animals showed an increase in cutaneous iron concentration as compared to normal mice. Papillomas were induced in mice skin by a single topical application of DMBA as initiator. A week after the initiation, promoting agent, croton oil was applied twice per week for 20 weeks. The appearance of the first tumor (papilloma), number of tumors/mouse and percentage incidence were recorded. When compared to the iron unloaded control and iron overload pregnant groups, the iron overload virgin animals showed an increased incidence of tumors. In iron overload virgin animals, tumors appeared earlier and also the numbers of tumors/mouse were significantly higher. However, in iron overload pregnant animals, diminished tumor incidence was observed and the numbers of tumors matched the result of normal pregnant animals. Our results show that iron overload in pregnant mice does not participate in the augmentation of DMBA- and croton oil-induced skin tumorigenesis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2000

Mechanism of ultraviolet B-induced cell cycle arrest in G2/M phase in immortalized skin keratinocytes with defective p53.

The ultraviolet B (UVB) portion (280-320 nm) of solar radiation is considered to be a major etiologic factor in human skin cancer and is a known cause of extensive DNA damage. In this study, we observed that UVB exposure of immortalized epidermal keratinocytes (HaCat cells) harboring mutant p53 leads to G(2)/M cell cycle arrest in both asynchronously growing and synchronized cells in a dose dependent manner. Following UVB exposure (200 mJ/cm(2)), we observed a threefold increase in G(2)/M population at 6 h, which increased to sixfold. The observed G(2)/M arrest was associated with an increase in cyclin B level whereas cdc2 protein remained unchanged. However, we observed an accumulation of tyrosine 15 hyperphosphorylated cyclin B-cdc2 complex. In addition, we observed an increase in chk1 kinase and a decrease in cdc25C protein levels. Chk1 phosphorylates cdc25C on serine 216 and inactivates it whereas cdc25C dephosphorylates tyrosine 15 phosphate of cdc2 and activates the cdc2-cyclin B complex. Therefore, the increase in chk1 and the decrease in cdc25C both participate in inhibiting the G2/M transition. Our data identifies two upstream targets leading to inhibition of cyclin B-cdc2 complexes, which explain the inhibition in cyclin B-associated cdc2 kinase following UVB exposure. The inactive phosphorylated cdc2-cyclin B complex remains sequestered in cytoplasm and may migrate to the nucleus following activation. Our data also indicate that UVB exerts unique effects in different types of skin keratinocytes having nonfunctional or mutant p53.

CDC2 Protein Kinase↗

PubMed2000

Induction of hepatic antioxidants in freshwater catfish (Channa punctatus Bloch) is a biomarker of paper mill effluent exposure.

Enzymatic and non-enzymatic antioxidants serve as an important biological defense against environmental oxidative stress. Information on antioxidant defense in fish is meager despite that fish are constantly exposed to a myriad of environmental stress including the oxidants. This study, therefore, assesses the activities of antioxidant enzymes viz., glutathione peroxidase, catalase and glutathione S-transferase and the non-enzymatic antioxidants viz., glutathione and metallothionein in various tissues of freshwater fish Channa punctatus (Bloch), in response to short-term and long-term exposures to paper mill effluent. The fish were exposed to the effluent at a concentration of 1.0% (v/v) for 15, 30, 60 and 90 days. The exposure caused a time-dependent increase in glutathione level (P < 0.001), activities of glutathione peroxidase (P < 0.05 to P < 0.001), glutathione S-transferase (P < 0.001) and a marginal initial decrease in catalase activity in the liver (P < 0.01 to P < 0.001). Metallothionein was induced in liver after 60 days of exposure. Two isoforms of metallothionein were detected. Catalase activity also increased 60 days afterwards. Antioxidant pattern was different in gill and kidney showing that liver was more resistant to oxidative damage as compared to gills and kidney. Our results demonstrate a pollutant-induced adaptive response in fish. In addition, levels of enzymatic and non-enzymatic tissue antioxidants may serve as surrogate markers of exposure to oxidant pollutants in fish.

Animals↗

PubMed2000

Pollutant-induced over-activation of phagocytes is concomitantly associated with peroxidative damage in fish tissues.

Pollutant-induced abnormal functioning of phagocytes and associated consequences were studied in freshwater catfish Heteropneustes fossilis (Bloch). Fish were exposed to effluent collected from bleached kraft type of paper mill at the concentration levels of 0.5, 1 and 2% for 15, 30, 60 and 90 days. Respiratory burst activity of peritoneal and head kidney phagocytes of exposed fish was measured by nitroblue tetrazolium reduction assay. Lipid peroxidation (LPO) was estimated in liver, gill and kidney of fish by measuring thiobarbituric acid reaction substances. It was observed that the phagocyte-activating xenobiotics of effluent induced an increase in the respiratory burst activity in phagocytes. The induction of respiratory burst activity was concomitantly associated with an increase in the peroxidative damage of tissues. The tissues most affected were kidney and gills. The change in LPO values in the gills of exposed fish was concentration- and time-dependent, showing significant increases (P<0.05 to <0.001) in all the exposed groups as compared with control fish. An almost similar pattern of LPO was observed in head kidney tissue (P<0.05 to <0.001). As regards liver, increase in LPO was not widespread, except at 0.5% for 90 days (P<0.05). In fact, reduced rates of LPO were observed in the livers of some groups. The results of respiratory burst corroborate with the phagocytic activation as well as with the extent of lipid peroxidation in the tissues, showing high population of circulatory phagocytes. Our results demonstrate that fish of polluted water are subjected to oxidative stress of multifarious dimensions.

Journal Article↗

PubMed2000

Green tea polyphenols and tannic acid act as potent inhibitors of phorbol ester-induced nitric oxide generation in rat hepatocytes independent of their antioxidant properties.

The deleterious effects of excessive release of nitric oxide (NO) have been implicated in the tissue damage and inflammation. In this study, the effect of various flavonoids and other oxidant scavenging chemical agents have been studied for their ability to inhibit 12-O-tetradecanoyl phorbol 13-acetate (TPA)-induced NO generation in rat hepatocyte. Hepatocytes activated with TPA (25-200 nM) released NO in a concentration- and time-dependent manner. Green tea polyphenols (GTP) and tannic acid (TA) were most effective in inhibiting TPA-induced NO generation (90%). These agents were also effective in inhibiting NO formation when added 2 h following TPA addition. The other oxidant scavengers, such as L-histidine, sodium azide, vitamin E and sodium benzoate, were not found to be effective even up to 1.0 mM concentration. These results suggest that TA and GTP are potent inhibitors of NOS activity and the inhibition of TPA-induced NO generation by these polyphenols is independent of their antioxidant activity. It is tempting to speculate that these agents could be utilized in the pharmacological manipulations of NO-dependent pathophysiological responses.

Animals↗

PubMed2000

Evaluation of the efficacy of Lawsonia alba in the alleviation of carbon tetrachloride-induced oxidative stress.

The hepatoprotective activity of the 50% ethanol extract of the bark of Lawsonia alba syn. L. inermis was investigated against the carbon tetrachloride-induced oxidative stress. Pretreatment of rats with doses of 250 and 500 mg/kg of the plant extract significantly (P < 0.001) lowered serum transaminases (GOT and GPT) and LDH levels, respectively, in a dose dependent manner against the significant (P < 0.001) rise of these damage marker enzymes when challenged with CCl4 (1 ml/kg, orally). Parallel to these changes, the plant extract prevented CCl4-induced oxidative stress by significantly maintaining the levels of reduced glutathione (GSH), its metabolizing enzymes and simultaneously inhibiting the production of free radicals. Pretreatment of rats with the extract also inhibited the peroxidation of microsomal lipids in a dose-dependent manner.

Animals↗

PubMed2000

In vitro inhibition of carcinogen-induced mutagenicity by Cassia occidentalis and Emblica officinalis.

Aqueous extracts of Cassia occidentalis Linn. (Leguminoceae) and Emblica officinalis Gaertn. (Euphorbiaceae) were screened for effectiveness in inhibiting mutagenicity of aflatoxin B1 (AFB1) and benzo[a]pyrene (B[a]P) in the Ames test. Antimutagenicity was evaluated using Salmonella typhimurium strains TA 98 and TA 100. In the assay, metabolic activation of AFB1 (0.5 microg/plate) and B[a]P (1 microg/plate) was mediated by rat liver S9 preparation. Although both plants inhibited mutagenicity, E. officinalis had more inhibitory effect than C. occidentalis. Their action is possibly mediated through interactions with microsomal activating enzymes. Their inhibitory action on chromosomal aberrations together with present results suggest that these plants have potent antimutagenic and anticarcinogenic activities against mutagens requiring metabolic activation.

Aflatoxin B1↗

PubMed2000

Novel approaches to chemoprevention of skin cancer.

Protection against sun-induced damage leading to photocarcinogenesis in skin is a highly desirable goal. Among various strategies, chemopreventive approaches utilizing non-toxic agents to prevent the occurrence of precancerous lesions or their surrogate markers are potentially attractive. Epidemiological and experimental studies provide evidence that some naturally occurring chemical agents in the human diet can diminish cancer risk. Aside from water, tea is the most common beverage consumed worldwide. Black tea accounts for nearly 80% of total tea production. Black tea and green tea are derived from the same plant, Camelia sinensis. Green tea contains monomeric polyphenols known as flavanols and black tea contains dimeric flavanols and polymeric polyphenols known as theaflavins (TFs) and thearubigins (TRs). Over the past fifteen years our laboratory has been exploring the feasibility of using tea and its constitutents as an approach to skin cancer prevention. We demonstrated that green tea, black tea and constituent polyphenols protect against chemical- and ultraviolet B (UVB)-induced carcinogenesis and reduce the growth of established tumors in skin. We have also shown the efficacy of green and black tea extracts against UVB and psoralen + ultraviolet A (PUVA)-induced early damage in skin. Although PUVA is highly effective in treating certain skin diseases, careful follow-up studies of cohorts of patients have shown that similar to UVB, PUVA treatment increases the risk for cutaneous squamous cell carcinoma and melanoma. We have found that oral administration of a standardized green tea extract (SGTE) prior to and during treatment of SKH-1 mice diminished PUVA-induced skin hyperplasia and hyperkeratosis. SGTE-treatment also inhibited PUVA-induced accumulation of c-fos and p53 proteins and epithelial hyperproliferation. Both topical application and oral administration of SGTE after PUVA-treatment reduced skin inflammation and cell hyperproliferation. Topical application of SGTE to human skin prior to PUVA-treatment inhibited the delayed skin inflammatory response. Similarly, oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic sub-fractions protect against UVB-induced erythema in SKH-1 mice. Furthermore, topical application of tea extracts to human volunteers protects against UVB-induced erythema. In summary, these studies indicate that tea extracts are effective in reducing UVB- and PUVA-mediated DNA damage, expression of early response genes and early inflammatory changes in skin. These studies verify a conceptual rationale for employing naturally occurring dietary constitutents as an approach to cancer chemoprevention.

Animals↗

PubMed2000

Inhibitory effect of Emblica officinalis on the in vivo clastogenicity of benzo[a]pyrene and cyclophosphamide in mice.

Benzo[a]pyrene (B[a]P) and cyclophosphamide (CP) are potent carcinogens/mutagens. Effect of Emblica officinalis extract administration on the in vivo genotoxicity of B[a]P and CP was studied using bone marrow chromosomal aberration and micronucleus induction tests in mice. Three doses (50, 250 and 500 mg/kg body weight) of the plant extract were administered orally for 7 consecutive days prior to the administration of single dose of mutagens (B[a]P 125 mg/kg oral; CP 40 mg/kg i.p.). It was found that administration of 250 and 500 mg/kg of E. officinalis extract significantly inhibited the genotoxicity of B[a]P as well as CP in both the assay systems. Administration of 50 mg/kg of the plant extract had no inhibitory effect. Vitamin C, a major constituent of E. officinalis when administered at dose level of 9 mg/kg b.w. (the approximate estimated amount present in the highest dose of plant extract, i.e. 500 mg) for 7 days did inhibit chromosomal aberrations and micronuclei induction, but not in a significant manner. Effect of administration of the abovementioned effective doses (250 and 500 mg/kg oral for 7 days) of plant extract and vitamin C (9 mg/kg oral for 7 days) on the hepatic activation and detoxification enzymes was also studied. Significant induction in the levels of glutathione content (GSH) and of antioxidant and detoxification enzymes viz., glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S transferase (GST) resulted from plant extract treatment to animals. On the other hand, cytochrome P 450 level was significantly decreased in the plant-extract-treated animals. There was no significant change in cytochrome P 450, GSH contents and activities of enzymes on treatment with vitamin C. The data indicate that the possible mechanism of inhibition by plant extract is mediated by its modulatory effect on hepatic activation and disposition processes.

Animals↗

PubMed1999

Evidence that ferric nitrilotriacetate mediates oxidative stress by down-regulating DT-diaphorase activity: implications for carcinogenesis.

Ferric nitrilotriacetate (Fe-NTA) is a known complete renal carcinogen as well as renal and hepatic tumor promoter, which acts by generating oxidative stress in the tissue. However, the mechanism by which it generates this stress is not fully understood. In this study, we show that Fe-NTA down-regulates hepatic and renal quinone reductase (QR) activity dose dependently. The maximum decrease in the activity of QR was observed at 12 h in the liver and 6 h in the kidney following Fe-NTA treatment. However, at all other time points studied, QR activity was reduced. In addition, a parallel increase in protein carbonyl content, a sensitive indicator of tissue oxidative stress was observed both in the liver and kidney. The pretreatment of animals with antioxidants, butylated hydroxyanisole and butylated hydroxytoluene, prevented the observed inhibition in the activity of QR and enhanced the formation of protein carbonyl in both organs. These studies suggest that Fe-NTA-mediated generation of oxidant free radicals down-regulates QR activity which may be responsible, at least in part, for the observed renal and hepatic injury and carcinogenic properties of Fe-NTA.

Animals↗

PubMed1999

Age-dependent renal accumulation of 4-hydroxy-2-nonenal (HNE)-modified proteins following parenteral administration of ferric nitrilotriacetate commensurate with its differential toxicity: implications for the involvement of HNE-protein adducts in oxidative stress and carcinogenesis.

In this study, we show that the toxicity of ferric nitrilotriacetate (Fe-NTA) can be correlated with the tissue accumulation of 4-hydroxy-2-nonenal (HNE)-modified protein adducts. It is observed that the toxic manifestations of Fe-NTA gradually increase with the increasing age of animals. A dose of Fe-NTA which produces almost 100% mortality in aged rats causes 70% mortality in adults, 30% in pups, 20% in litters, and less than 10% in neonates. The age-dependent increase in its toxicity is also evident from the data of renal microsomal lipid peroxidation and hydrogen peroxide generation. No significant difference in the generation of H2O2 and induction of renal microsomal lipid peroxidation between saline- and Fe-NTA-treated neonates, litters, and pups could be observed. However, in adult rats, a significant increase in both of the parameters was observed which was even greater in aged rats. On the contrary, renal glutathione levels in these animals show an inverse relationship with the oxidant generation. In neonates, litters, and pups the maximum decrease of glutathione was up to 22%, whereas in adult and aged rats, the depletion was more than 60% of their respective saline-treated controls. Parallel to this data, blood urea nitrogen and creatinine, the indicators of renal damage, show a significant increase in Fe-NTA-treated adult and aged rats only, whereas no significant alterations were observed in other groups. Similarly, the magnitude of ODC induction and [3H]thymidine incorporation was much higher in aged and adult rats in comparison to other groups of animals after Fe-NTA treatment. Additionally, the immunohistochemical localization studies show a significant increase in HNE-modified protein adducts in kidney of adult and aged rats, whereas no significant staining was observed in other groups. A similar increase in the level of protein carbonyls has also been observed with the increasing age of rats. These data suggest that the toxicity of Fe-NTA increases with the increasing age of rats and correlates with the accumulation of HNE-modified protein adducts. It may also be speculated that Fe-NTA-mediated renal toxicity leading to carcinogenesis may be related to the tissue accumulation of HNE-modified protein adducts. However, further studies are needed to establish a definite role of HNE-modified proteins in Fe-NTA-mediated carcinogenesis.

Aging↗