Biomedical subjects

M Athar

Publications and source records attributed to M Athar.

At least 37 records · Page 2Linked to original sources

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↗

PubMed1999

The baculovirus antiapoptotic p35 gene also functions via an oxidant-dependent pathway.

Cellular imbalance in the levels of antioxidants and reactive oxygen species resulting in apoptosis is directly associated with a number of parasitic infections, aging, and several genetic and multifactorial diseases. The baculovirus AcNPV-encoded antiapoptotic p35 gene prevents apoptosis induced by a variety of apoptotic agents in different systems. We demonstrate the ability of the p35 gene to inhibit oxidative stress-induced apoptosis. In vitro cultured Spodoptera frugiperda (Sf9) insect cells infected with wild-type AcNPV carrying the antiapoptotic p35 gene did not undergo apoptosis when subjected to oxidative stress generated by the exogenous application of oxidants or in vivo generation of reactive oxygen species or on direct exposure of cells to UV radiations. An AcNPV mutant carrying a deletion of the p35 gene failed to arrest cell death. Transfection of cells with a recombinant plasmid containing the p35 gene under the transcriptional control of a stress promoter (Drosophila hsp70) was also able to rescue cells from oxidative stress-induced cell death, demonstrating the direct involvement of P35. ESR spin-trapping studies conducted in vitro and in vivo demonstrated that P35 functions directly as an antioxidant by mopping out free radicals and consequently prevents cell death by acting at an upstream step in the reactive oxygen species-mediated cell death pathway.

Animals↗

PubMed1999

Potassium bromate (KBrO3) induces renal proliferative response and damage by elaborating oxidative stress.

Many chemical compounds which induce oxidative stress in the tissue produce carcinogenesis either alone or act as a tumor promoter in carcinogen-initiated animals after prolonged exposure. Here, we report that potassium bromate (KBrO3) induces renal proliferative response and damage by elaborating oxidative stress. KBrO3 administration dose dependently induced renal ornithine decarboxylase (ODC) activity several fold compared to its activity in saline-treated rats. Similarly renal DNA synthesis which has been measured as [3H]thymidine incorporation in DNA also increases. KBrO3 administration also depleted the level of renal glutathione and glutathione reductase activity in a time dependent manner. The maximum depletion in the levels of renal glutathione and glutathione reductase activity was observed 3 h after KBrO3 treatment which was 60 and 40%, respectively, of saline-treated controls. Parallel to these changes, a sharp increase in the blood urea nitrogen and serum creatinine levels was observed which is indicative of the concurrent renal damage. These results suggest that oxidant generating KBrO3 acts as a potent proliferator of kidney and acts by producing oxidative damage.

Animals↗

PubMed1999

Reconstituted 3-dimensional human skin as a novel in vitro model for studies of carcinogenesis.

EpiDerm (MatTek Co., MA) is a reconstituted human skin equivalent which exhibits morphological and growth characteristics similar to human skin. This model has previously been utilized to evaluate the cytotoxicity and irritant potential of various cosmetic and household products. In this study, we show for the first time that EpiDerm can be used successfully to evaluate the genotoxicity of different types of known carcinogenic agents such as benzo[a]pyrene (BaP), ultraviolet B radiation (UVB), ultraviolet A radiation (UVA), and psoralen-ultraviolet A radiation (PUVA) at the molecular level. The topical application of 50 microg/cm2 BaP to EpiDerm resulted in the accumulation of BaP-DNA adducts and c-fos and p53 proteins as evidenced by immunohistochemical localization. Similarly, exposure to UVB (50 mJ/cm2) and UVA (2.5 J/cm2) enhanced the epidermal expression of c-fos and p53 proteins in the human skin equivalent. PUVA treatment of EpiDerm, however, resulted in the formation of both DNA-8-MOP adducts and augmented expression of c-fos and p53 proteins. Most of these changes reached a peak 8 h after the treatments except in the case of UVA where maximum changes in the expression of c-fos and p53 proteins were observed 24 h after treatment. These results are similar to those previously reported in human and murine skin following exposure to BaP, UVB, UVA, or PUVA indicating that human skin equivalents can be used as a convenient and cost-effective alternative to animal testing for assessing the genotoxicity and mechanism of action of mutagens/carcinogens in human skin.

Culture Techniques↗

PubMed1999

Augmentation of 12-O-tetradecanoyl 13-phorbol acetate-mediated tumor promoting response by the porphyrin photosensitization of 7,12-dimethyl benz[a]anthracene-initiated murine skin: role of in situ generated reactive oxygen species.

Recently, we have shown that sustained ROS generation by prolonged porphyrin-mediated photosensitization in murine skin acts as a stage I and weak complete tumor promoter. Further to this, in the present study, we show that porphyrin photosensitization of DMBA-initiated murine skin results in the augmentation of TPA-mediated tumor promoting response. The photosensitization increased tumor yield to 15 tumors per mouse as compared to 7.5 tumors per mouse in the group treated with TPA alone. Further, 100% tumor incidence in the TPA-treated photosensitized group occurred at week 11 whereas it occurred at week 19 in the TPA alone treated group. Porphyrin photosensitization slightly decreased the latency period of TPA-mediated tumor formation by 1 week. The TPA-mediated ODC induction (1300% of saline-treated control) has been augmented in the photosensitized group (1950%). However, the amount of [3H]thymidine incorporation was not significantly different in the photosensitized TPA-treated and TPA alone-treated groups. Similarly, TPA treatment in photosensitized animals augmented the depletion of cutaneous glutathione and enhancement of lipid peroxidation. These changes were attenuated in butylated hydroxytoluene-pretreated animals. Our results suggest that cutaneous porphyrin photosensitization augments TPA-mediated tumor promotion in murine skin.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1999

Green tea protects against psoralen plus ultraviolet A-induced photochemical damage to skin.

The use of psoralens combined with exposure to ultraviolet A radiation is a major form of treatment for psoriasis and a number of other common skin diseases. Although psoralen plus ultraviolet A treatment is highly effective, careful follow-up cohort studies have shown that it greatly increases risk for the development of cutaneous squamous cell carcinoma and melanoma. Strategies to reduce the risk of cancer development in psoralen plus ultraviolet A-treated populations are highly desirable. In prior studies, we demonstrated that green tea and constituent polyphenols protect against ultraviolet B-induced carcinogenesis and reduce the growth rate of established tumors in skin. In this study, we show that pre- and post-treatment with standardized green tea extract in psoralen plus ultraviolet A treatment populations abrogates the psoralen plus ultraviolet A-induced photochemical damage to skin. Intact mouse and human skin and reconstituted human skin were employed to assess the effect of both topical and oral administration of standardized green tea extract against psoralen plus ultraviolet A-induced photodamage. Oral administration of standardized green tea extract prior to and during multiple psoralen plus ultraviolet A treatments reduced hyperplasia and hyperkeratosis in murine skin. Standardized green tea extract treatment also inhibited accumulation of c-fos and p53 protein induction following a single exposure to psoralen plus ultraviolet A. c-fos and p53 positive cells in psoralen plus ultraviolet A-treated skin were found to be increased by 55.4 +/- 13. 6% and 62.3 +/- 10.5%, respectively, compared with saline-treated unexposed control skin. Oral administration of 0.4 or 0.8% standardized green tea extract inhibited c-fos protein accumulation by 18.5% and 46.2% (p < 0.05), respectively, and p53 protein accumulation by 26.1% and 54.3% (p < 0.05), respectively. Similarly proliferating cell nuclear antigen staining, a marker of cell proliferation was induced (73.7%) in psoralen plus ultraviolet A-treated skin. Oral administration of 0.4% or 0.8% standardized green tea extract 1 d after psoralen plus ultraviolet A treatment was effective in reducing psoralen plus ultraviolet A-induced inflammatory responses including erythema and edema formation. When standardized green tea extract was applied to EpiDerm, a reconstituted human skin equivalent, psoralen plus ultraviolet A-induced 8-methoxypsoralen-DNA adduct formation and p53 protein accumulation were inhibited. Topical application of 0.2 mg 8-methoxypsoralen per cm2 followed by exposure to ultraviolet A (2.5 J per cm2) resulted in delayed erythema formation in human subjects. Pretreatment of human skin with topical application of 0.2 mg standardized green tea extract per cm2 30 min prior to psoralen plus ultraviolet A treatment resulted in an almost complete abrogation of psoralen plus ultraviolet A-induced erythema. In summary, these data demonstrate that standardized green tea extract protects against psoralen plus ultraviolet A-induced phototoxicity by inhibiting DNA damage and diminishing the inflammatory effects of this modality.

Animals↗

PubMed1999

Glutathione redox system in oxidative lung injury.

Glutathione (GSH) is a ubiquitous intracellular thiol present in all tissues, including lung. Besides maintaining cellular integrity by creating a reduced environment, GSH has multiple functions, including detoxification of xenobiotics, synthesis of proteins, nucleic acids, and leukotrienes. Present in high concentrations in bronchoalveolar lavage fluid (BALF), GSH provides protection to the lung from oxidative injury induced by different endogenous or exogenous pulmonary toxicants. Its depletion in the lung has been associated with the increased risk of lung damage and disease. The redox system of GSH consists of primary and secondary antioxidants, including glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), and glucose 6-phosphate dehydrogenase (G6PD). Alterations in the activities of these enzymes may reflect reduced cellular defense and may serve as surrogate markers of many lung diseases. As GSH is also involved in the regulation of expression of protooncogenes and apoptosis (programmed cell death), the development of diseases such as cancer and human immune deficiency may be affected by depleting or elevating cellular GSH levels. Exogenous delivery of GSH or its precursor N-acetyl cysteine (NAC) is being used as chemotherapeutic approach.

Antioxidants↗

PubMed1999

Nordihydroguairetic acid is a potent inhibitor of ferric-nitrilotriacetate-mediated hepatic and renal toxicity, and renal tumour promotion, in mice.

Ferric-nitrilotriacetate (Fe-NTA) is a known renal carcinogen. In the present study, we report the effect of a potent lignin-derived herbal antioxidant, nordihydroguairetic acid (NDGA), against Fe-NTA-mediated tissue toxicity. Fe-NTA (alone) treatment of mice enhances ornithine decarboxylase activity to 259% in liver and 341% in kidney and increases [3H]thymidine incorporation in DNA to 250% in liver and 324% in kidney compared with the corresponding saline-treated controls. The enhanced ornithine decarboxylase activity and DNA synthesis showed a reduction to 138 and 123%, respectively, in liver at a higher dose of 2 mg NDGA/day/animal whereas in kidney the reduction was to 118 and 102%, respectively, compared with the corresponding saline-treated controls. In the Fe-NTA (alone)-treated group, a 12% renal tumour incidence was recorded whereas, in N-diethylnitrosamine (DEN)-initiated and Fe-NTA-promoted animals, the percentage tumour incidence was increased to 68% as compared with untreated controls. No tumour incidence was recorded in the DEN-initiated, non-promoted group. The administration of NDGA, afforded >80% protection against DEN- and Fe-NTA-mediated renal tissue injury in vivo. Fe-NTA treatment also enhanced hepatic and renal microsomal lipid peroxidation to 170 and 205% of saline-treated controls, respectively, and hydrogen peroxide generation by >2.5-fold in both tissues accompanied by a 51 and 21% decrease in the level of glutathione and 35-48 and 35-50% decrease in the activities of glutathione-metabolizing and antioxidant enzymes in liver and kidney, respectively. These changes were reversed significantly in animals receiving a pre-treatment of NDGA. Our data show that NDGA can abrogate the toxic and tumour-promoting effects of Fe-NTA in liver and kidney of mice and can serve as a potent chemopreventive agent to suppress oxidant-induced tissue injury and tumorigenesis.

Animals↗

PubMed1999

Glyceryl trinitrate, a nitric oxide donor, suppresses renal oxidant damage caused by potassium bromate.

Nitric oxide (NO) is a short-lived, readily diffusible intracellular messenger molecule associated with multiple organ-specific regulatory functions. Endogenous stimulation or exogenous administration of NO have been shown to inhibit production of reactive oxygen species (ROS) and expression of oxidant-mediated molecular or tissue injury. Potassium bromate (KBrO3) is one such potent renal oxidant that acts through generation of ROS-mediated lipid peroxidation, and causes increased ornithine decarboxylase activity, enhanced rate of DNA synthesis and depletion of the antioxidant armoury of the tissue. In this study, we elucidate the effect of exogenous NO administration, using the NO donor glyceryl trinitrate (GTN), on KBrO3-induced nephrotoxicity, oxidative stress and cell proliferation. KBrO3 administration at a dose of 125 mg/kg body weight results in significant (P < 0.001) depletion in renal glutathione (GSH) content, and glutathione reductase (GR) activity with a concomitant increase in microsomal lipid peroxidation, and blood urea nitrogen (BUN) and creatinine levels. Parallel to these changes, we found significant enhancement in ornithine decarboxylase (ODC) activity and rate of renal DNA synthesis. Subsequent administration of GTN resulted in dose-dependent amelioration of GSH content and GR activity with concomitant inhibition of lipid peroxidation, and BUN and creatinine levels. In addition, GTN administration to KBrO3-intoxicated rats resulted in significant dose-dependent down regulation of enhanced ODC activity and rate of [3H]-thymidine incorporation in renal DNA, providing support for the protective role of NO in attenuation of KBrO3-induced oxidative stress and cell proliferation. Enhancement of oxidative tissue injury and cell proliferation on administration of the NO inhibitor, L-NAME, further demonstrates the protective efficacy of endogenous NO. These data suggest that NO inhibits KBrO3-induced tissue injury, oxidative stress and proliferative response in the rat kidney.

Animals↗

PubMed1999

Ellagic acid ameliorates nickel induced biochemical alterations: diminution of oxidative stress.

Nickel, a major environmental pollutant is known for its clastogenic, toxic and carcinogenic potentials. The present investigation shows that ellagic acid proves to be exceptional in the amelioration of the nickel-induced biochemical alterations in serum, liver and kidney. Administration of nickel (250 micromol Ni/kg body wt) to female Wistar rats, resulted in increase in the reduced glutathione (GSH) content [kidney (*P<0.05) and liver (**P<0.001)] and Glutathione-S-transferase (GST) and glutathione reductase (GR) activities [kidney and liver, (**P<0.001)]. Ellagic acid treatment to the intoxicated rats leads to the formation of soluble ellagic acid-metal complex which facilitates excretion of nickel from the cell or tissue, thus ameliorating nickel-induced toxicity, as evident from the down regulation of GSH content, GST and GR activities with concomitant restoration of glutathione peroxidase (GPx) activity in liver and kidney. Our data shows that ellagic acid maintains cell membrane integrity through sequestration of metal ions from the extracellular fluid, as evident from the alleviated levels of serum glutamate oxaloacetate transaminase, (SGOT), serum glutamate pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH) when compared to nickel treated group. Similarly, the enhanced blood urea nitrogen (BUN) and serum creatinine levels that are indicative of renal injury showed a reduction of about 45 and 40%, respectively. The data also show that treatment of ellagic acid after 30 min of nickel administration exhibits maximum inhibition in a dose-dependent manner. In summary, our data suggests that ellagic acid act as an effective chelating agent in suppressing nickel-induced renal and hepatic biochemical alterations.

Animals↗

PubMed1999

Photoprotective effect of black tea extracts against UVB-induced phototoxicity in skin.

In previous studies, we showed that green tea and black tea extracts and their major polyphenolic constituents protect against UVB light-induced carcinogenesis in murine skin. All of these studies required chronic administration of tea extracts or specific constituents either topically or orally. However, it is not known whether acute or subchronic administration of black tea extracts or constituents can ameliorate UVB-induced early effects in skin. In the present study, cultured keratinocytes and mouse and human skin were employed to assess the effect of both oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic subfractions namely BTF1 and BTF2 against UVB-induced photodamage. In SKH-1 hairless mice, topical application of SBTE (0.2 mg/cm2) prior to UVB exposure (180 mJ/cm2) resulted in 40% reduced incidence and 64% reduced severity of erythema and 50% reduction in skinfold thickness by day 6 when compared to nontreated UVB-exposed animals. The SBTE was also effective in protecting against UVB-induced erythema in human volunteers. Administration of SBTE 5 min after UVB irradiation was similarly effective in reducing UVB-induced inflammation in both murine and human skin. The major polyphenolic subfractions, BTF1 and BTF2, were also effective in protecting in mouse skin. The SBTE subfractions inhibited UVB-induced tyrosine phosphorylation of epidermal growth factor receptor (EGFR). The UVB irradiation of human epidermoid carcinoma cells resulted in 3.3-fold induction of tyrosine phosphorylation of EGFR. Pretreatment with BTF1 and BTF2 reduced tyrosine phosphorylation of EGFR by 53% and 31%, respectively. The UVB-mediated enhanced expression of the early response genes, c-fos and c-jun in human epidermal keratinocytes was reduced in a dose-dependent manner by SBTE. Topical application of SBTE was also effective in reducing accumulation of c-fos and p53 proteins by 82% and 78%, respectively, in UVB-exposed mouse skin. These data provide evidence that constituents of black tea can abrogate UVB-induced erythema and associated early events in murine and human skin.

Administration, Oral↗

PubMed1999

Protective effect of Cassia occidentalis extract on chemical-induced chromosomal aberrations in mice.

This study was conducted to determine the antimutagenic potential of aqueous extract of Cassia occidentalis against the chromosomal aberrations (CA) produced in vivo by benzo[a]pyrene (B[a]P) and cyclophosphamide (CP) in mice. Animals (male mice) were treated with three doses of plant extract (50 mg/kg, 250 mg/kg and 500 mg/kg) for 7 days prior to the administration of single dose of mutagens (B[a]P 125 mg/kg oral; CP 40 mg/kg i.p.). The results indicated that C. occidentalis was not genotoxic per se and exerted no other toxic signs and symptoms in treated animals. The chromosomal aberrations produced by B[a]P and CP were significantly reduced (p < 0.001) by C. occidentalis pre-treatment. Furthermore, animals treated with plant extract showed a reduced level of cytochrome P 450 (Cyt P 450) and elevated levels of glutathione S-transferase (GST) activity and glutathione content in the liver. It seems that C. occidentalis exerts its antimutagenic activity by modulating the xenobiotic activation and detoxification mechanisms.

Animals↗

PubMed1999

Copper-nitrilotriacetate (Cu-NTA) is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen.

Earlier we have shown that ferric-nitrilotriacetate (Fe-NTA) is a hepatic as well as renal tumor promoter and acts by elaborating oxidative stress. In this study we show that copper-nitrilotriacetate (Cu-NTA) is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen. Similar to Fe-NTA, Cu-NTA has an ability to induce hepatic ornithine decarboxylase (ODC) activity dose-dependently. The maximum induction in hepatic ODC activity was observed 12 h after Cu-NTA treatment. However, renal ODC activity showed no significant changes at any time point and dose regimen studied. Similarly, hepatic and renal DNA synthesis which are measured as [3H]thymidine incorporation were increased dose-dependently in both the organs after Cu-NTA treatment. Unlike Fe-NTA, Cu-NTA administration had no significant effect on hepatic and renal glutathione, and on the activities of glutathione reductase, glutathione-S-transferase and catalase. In liver, saline-alone, DEN-alone, Cu-NTA-alone or DEN + Cu-NTA treated animals showed no hepatic tumors. Liver histology from only DEN-initiated and saline-treated control animals showed occasional appearance of a typical cell with large nucleus. Treatment of Cu-NTA to uninitiated and initiated animals showed more or less similar hepatic histology. Treatment of Cu-NTA to DEN-initiated animals resulted in the proliferative changes characterized by extensive hepatocellular hyperplasia. In case of kidney, the treatment of Cu-NTA to both the DEN-initiated and uninitiated animals led to the development of renal cell tumors. Treatment of Cu-NTA to the uninitiated animals produced renal cell tumors in about 18.7% animals. However, treatment of Cu-NTA to the DEN-initiated animals led to the development of renal cell tumors in 77.7% animals, of which most of the tumors were bilateral. However, DEN-initiated and saline-treated control animals showed no evidence of tumors. Our data indicate that Cu-NTA is a potent inducer of proliferative response both in liver and kidney but is a complete renal carcinogen.

Animals↗

PubMed1998

Susceptibility to the biological effects of polyaromatic hydrocarbons is influenced by genes of the major histocompatibility complex.

Polyaromatic hydrocarbons are ubiquitous environmental chemicals that are important mutagens and carcinogens. The purpose of this study was to determine whether genes within the major histocompatibility complex (MHC) influence their biological activities. Cell-mediated immunity to dimethylbenz(a)anthracene (DMBA) was investigated in congenic strains of mice. On three different backgrounds, H-2(k) and H-2(a) haplotype mice developed significantly greater contact-hypersensitivity responses to DMBA than H-2(b), H-2(d), and H-2(s) mice. In B10.A(R1) mice, which are Kk and Id, a vigorous contact-hypersensitivity response was present, indicating that the response was governed by class I, rather than class II, MHC genes. C3H/HeN (H-2(k)) and C3H.SW (H-2(s)) strains were also compared for the development of skin tumors and the persistence of DMBA-DNA adducts. When subjected to a DMBA initiation, phorbol 12-tetradecanoate 13-acetate (TPA)-promotion skin-tumorigenesis protocol, C3H/HeN mice, (which develop cell-mediated immunity to DMBA) were found to have significantly fewer tumors than C3H.SW mice (a strain that failed to develop a cell-mediated immune response to DMBA). DMBA-DNA adducts were removed more rapidly in C3H/HeN than in C3H.SW mice. The results indicate that genes within the MHC play an important role in several of the biological activities of carcinogenic polyaromatic hydrocarbons. The observations are consistent with the hypothesis that cell-mediated immunity to chemical carcinogens serves to protect individuals by removing mutant cells before they can evolve into clinically apparent neoplasms.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1998

Effect of iron overload on the benzoyl peroxide-mediated tumor promotion in mouse skin.

In this communication, we report that iron overload augments benzoyl peroxide (BPO)-mediated tumor promotion in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. Female albino Swiss mice were overloaded with iron and tumors were initiated by applying a single topical application of DMBA. A week after the initiation, promoting agent, BPO, was applied three times/week for 46 weeks. The appearance of the first tumor (papilloma) and the number of tumors/mouse were recorded. When compared to the control group, the iron-overloaded mice showed an increased incidence of tumors at various time intervals. In iron-overloaded animals, tumors appeared earlier and also the number of tumors/mouse was significantly higher. These data could be correlated with the iron levels of mouse skin in the two groups. Further, BPO-mediated induction in ornithine decarboxylase (ODC) activity and [3H]thymidine incorporation in cutaneous DNA were higher in the iron overload group. In addition, in iron-overloaded mice, cutaneous lipid peroxidation (LPO) and xanthine oxidase (XOD) activities were higher, whereas catalase activity was reduced. Similar to papilloma induction, a significant increase in carcinoma yield and incidence was observed in iron-overloaded animals. Based on this study, we propose that iron overload significantly increases the tumor promotion and progression potential of BPO. We suggest that oxidative stress generated by iron overload is responsible for the augmentation of BPO-mediated cutaneous tumorigenesis.

9,10-Dimethyl-1,2-benzanthracene↗