Begell House Inc.
Journal of Environmental Pathology, Toxicology and Oncology
JEP(T)
0731-8898
21
1
2002
Mechanisms of Carcinogenicity of Aryl Hydrazines, Aryl Hydrazides, and Arenediazonium Ions
31
10.1615/JEnvironPatholToxicolOncol.v21.i1.10
Jeannine H.
Powell
Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Moreantown, WV
Peter M.
Gannett
Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Moreantown, WV.
Aryl hydrazines carcinogenesis has been studied for over 25 years and remains poorly understood, although most aryl hydrazines are toxic, tumorigenic, or carcinogenic. In this article, aryl hydrazine cardnogenesis is reviewed comprehensively. The relevant chemistry and biochemistry of aryl hydrazines are first addressed and provide the framework for understanding how aryl hydrazines are metabolized, the reactive intermediates that are produced, and the biological reactive intermediates and products that are formed. Issues of DNA damage, mutagenicity, and enzyme activation are next addressed followed by a brief review of aryl hydrazine tumorigenicity studies. Because several related substrates are metabolized to the same intermediates as are aryl hydrazines, they are briefly discussed. The review concludes with a short discussion of the possible mechanism of cardnogenesis by aryl hydrazines.
In Vitro Protective Effects of Terminalia arjuna Bark Extracts Against the 4-Nitroquinoline-N-Oxide Genotoxicity
12
10.1615/JEnvironPatholToxicolOncol.v21.i1.20
Rossana
Pasquini
Department of Hygiene, University of Perugia, Perugia, Italy
Giuseppina
Scassellati-Sforzolini
Department of Hygiene, University of Perugia, Perugia, Italy
Milena
Villarini
Department of Hygiene, University of Perugia, Italy
Massimo
Moretti
Department of Hygiene, University of Perugia, Italy
Massimiliano
Marcarelli
Department of Hygiene, University of Perugia, Perugia, Italy
Cristina
Fatigoni
Department of Hygiene, University of Perugia, Perugia, Italy
Satwinderjeet
Kaur
Department of Botanical Sciences, Guru Nanak Dev University, Amritsar, India
Subodh
Kumar
Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab, India
Iqbal S.
Grover
Department of Botanical Sciences, Guru Nanak Dev University, Amritsar, India
We determined the antimutagenic potential of chloroform, acetone, methanol, methanol+HCl, diethyl ether, and ethyl acetate extracts of Terminalia arjuna bark against the model mutagen 4-nitroquinoline-N-oxide (4-NQO) using the Salmonella/microsome, comet, and micronucleus (MN) tests. Salmonella typhimurium TA100 strain and human peripheral white blood cells were coincubated with various concentrations (from 5 to 500 mg) of the six extracts and 4-NQO (from 0.05 to 2 mg). We found that the 4-NQO mutagenicity was inhibited by more than 70% in the Salmonella/microsome test at the highest nontoxic extract dose of ethyl acetate (50 mg/plate), chloroform (100 (mg/plate), acetone, (100 (mg/plate), and methanol (500 (mg/plate). A less marked antimutagenicity activity (inhibition of about 40—45%) was observed for the acidic methanol and diethyl ether extracts. The comet assay showed that acetone extract (100 mg/mL) was more effective in reducing the DNA damage caused by 4-NQO (ca. 90%), whereas the chloroform, ethyl acetate, and diethyl ether extracts were cytotoxic. In the MN test, the decrease in 4-NQO clastogenicity was observed by testing the mutagen especially with chloroform and ethyl acetate extracts (inhibition about 40-45%). The acetone and methanol extracts showed a less marked activity (33% and 37%, respectively). The results of the present study suggest that T. arjuna bark contains some nonpolar as well as polar compounds with antimutagenic activity against 4-NQO. Several explanations can be suggested, but further investigations are necessary to definitely identify the active compounds.
Modulatory Effect of Phenolic Fractions of Terminalia arjuna on the Mutagenicity in Ames Assay
12
10.1615/JEnvironPatholToxicolOncol.v21.i1.30
Kamaljit
Kaur
Department of Botanical Sciences, Guru Nanak Dev University, Amritsar, Punjab, India
Saroj
Arora
Department of Botanical Sciences, Guru Nanak Dev University, Amritsar 143 005, Punjab, India
Subodh
Kumar
Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab, India
Avinash
Nagpal
Department of Botanical Sciences, Guru Nanak Dev University, Amritsar, India
We determined the antimutagenicity of phenolic fractions of Terminalia arjuna (soluble and insoluble in chloroform) against two direct-acting mutagens, 4-nitro-o-phenylenediamine (NPD) and sodium azide, and against the S9-dependent mutagen 2-aminofluorene (2AF), in TA98 and TA100 tester strains of Salmonella typhimurium. We found that the phenolic fractions of T. arjuna inhibited revertants induced by the S9-dependent mutagen more remarkably than the direct-acting mutagens. Furthermore, the phenolic fractions showed maximum inhibition of 98% and 101.55%, respectively, in the pre-incubation mode of treatment against the mutations induced by 2AF. Overall, the fractions inhibited the revertants induced by S9-dependent mutagens more effectively than those induced by direct-acting mutagens. The percentage of inhibition was higher in the pre-incubation than with direct acting mutagens. The fraction insoluble in chloroform showed more inhibition than the soluble one, which corresponds to a higher polyphenol content in the insoluble fraction than in the soluble extract.
DNA Single Strand Breaks Induced by Low Levels of Occupational Exposure to Styrene: The Gap between Standards and Reality
5
10.1615/JEnvironPatholToxicolOncol.v21.i1.40
Magdy Y.
Shamy
High Institute of Public Health, Occupational Health Department, Alexandria University, Alexandria, Egypt
Hazem H.
Osman
Faculty of Sciences, Biochemistry Department, Alexandria University, Alexandria, Egypt
Kamal M.
Kandeel
Faculty of Sciences, Biochemistry Department, Alexandria University, Alexandria, Egypt
Nehad M.
Abdel-Moneim
Faculty of Sciences, Biochemistry Department, Alexandria University, Alexandria, Egypt
Khalid F. El
Said
High Institute of Public Health, Occupational Health Department, Alexandria University, Alexandria, Egypt
Styrene is a known mutagen and suspected carcinogen, used in the reinforced plastic industry. This study aims to identify the occurrence of DNA single strand breaks (SSBs) in workers exposed to styrene levels far below the recommended standards. We compared 26 exposed workers with 26 control subjects and found a significant increase in the incidence of DNA-SSBs in the exposed individuals. The levels of the biological indices of exposure (urinary mandelic and phenyl glyoxylic acids) were less than 25% of the recommended limits. Reduction of the threshold limit values/time-weighted-average (TLV-TWA) applied is strongly recommended.
Studies on Sister Chromatid Exchanges in Peripheral Lymphocytes of Spray Painters
3
10.1615/JEnvironPatholToxicolOncol.v21.i1.50
Palanivel
Gajalakshmi
Department of Genetics, Dr. ALMPGIBMS, University of Madras, Taramani Chennai, India
Protima
Mallick
Department of Genetics, Dr. ALMPGIBMS, University of Madras, Taramani Chennai, India
Perumal
Venkatesan
Department of Statistics, Tuberculosis Research Centre, ICMR, Chetpet, Chennai, India
Sathyaveedu Thiagarjan
Santhiya
Department of Genetics, Dr. ALMPGIBMS, University of Madras, Taramani Chennai, India
Arabandi
Ramesh
Department of Genetics, Dr. A. L. Mudaliar Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Chennai 600 113, India
In a comparative study of sister chromatic! exchanges (SCEs) in cultured lym-phocytes, we evaluated the genotoxic risk in 104 male spray painters employed in repair workshops in Chennai City, India, and 50 matched healthy, unexposed controls. We found a higher frequency of SCEs among painters (3.74 ± 0.11, X ± SE) than among controls (2.15 ± 0.08), and among smoking painters (4.03 ± 0.21) than among nonsmoking painters (3.55 ±0.13), with no significant difference in controls (smokers: 2.1 ± 0.2; nonsmokers: 2.2 ± 0.1). Alcoholism did not contribute to an increased SCE frequency. Stepwise multiple linear regression analysis on painters showed that duration of service, smoking, and alcoholism significantly affected SCE scores and explained the 14% variation observed.
Expression of Telomerase Reverse Transcriptase in Radiation-Induced Chronic Human Skin Ulcer
4
10.1615/JEnvironPatholToxicolOncol.v21.i1.60
Po
Zhao
Department of Pathology, Chinese Department of Pathology, Chinese General Hospital of People's Liberation Army, 28 Fuxing Road, 100853, Beijing, China
Li
Zhijun
Department of Pathology, Chinese General Hospital of People's Liberation Army, Beijing, China
Mei
Zhong
Department of Pathology, Chinese General Hospital of People's Liberation Army, Beijing, China
Qingyang
Gu
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Dewen
Wang
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
The objective of this study was to investigate the expression of the catalytic subunit of telomerase, telomerase reverse transcriptase (TRT), and the possible relationship between the TRT expression and poor healing or cancer transformation in radiation-induced chronic human skin ulcer. Rabbit antibody to human TRT and SP immunohistochemical method were used to detect TRT expression in 24 cases of formalin-fixed, paraffin-embedded chronic human skin ulcer tissues induced by radiation, 5 cases of normal skin, 2 of burned skin, and 8 of cancer. The positive rate of TRT expression in chronic radiation ulcers was 58.3% (14/24), of which it was strongly positive in 41.7% cases (10/24) and weakly positive in 16.7% (4/24). TRT expression was 0% in normal (0/5) and burned skin (0/2), and 100% in cancer cases (8/8). The strongly positive expression of TRT was observed almost always in the cytoplasm and nucleus of squamous epithelial cells of the epidermis but it was negative or only weakly positive in the smooth muscle and endothelia of small blood vessels and capillaries, and in fibroblasts. Chronic inflammatory cells, plasmacytes, and lymphocytes were weakly positive for TRT. TRT expression could be involved in the poor healing caused by sclerosis of small blood vessels and lack of granulation tissue and in the cancer transformation of chronic radiation ulcer.
Expression of MMP1 in Surgical and Radiation-Impaired Wound Healing and Its Effects on the Healing Process
8
10.1615/JEnvironPatholToxicolOncol.v21.i1.70
Qingyang
Gu
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Dewen
Wang
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Yabing
Gao
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Jie
Zhou
Institute of Microbiology and Epidemiology, Academy or Military Medical Sciences, Beijing, China
Ruiyun
Peng
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Yufang
Cui
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Guowei
Xia
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Quanhong
Qing
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Hong
Yang
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Jie
Liu
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Meilan
Zhao
Department of Pathology, Beijing Institute of Radiation Medicine, Beijing, China
Radiation-impaired wound is characterized by delayed healing, nonhealing, and carcinogenesis. The mechanism remains unclear. Matrix metalloproteinases (MMPs) are one family of key regulators of the process of wound healing. Their abnormal expression plays important roles in the formation of some chronic skin ulcers. The objective of this project was to study the expression of MMP1 in surgical and radiation-impaired wound healing and its effects on the healing process and tissue remodeling. A rat model of radiation-impaired wound healing was used. Routine light microscopy, electron microscopy, immunohistochemistry, and in situ hybridization, all of which enabled the detection of MMPI expression during the healing process, were performed. The wound healing process was impaired and delayed. In rats receiving 25Gy g-ray locally, the irradiated wounds healed 6 days later than the nonirradiated controls. The following changes in MMP1 expression were found: (1) In the early inflammatory phase and in the period of granulation tissue formation, MMP1 expression was only slightly if at all affected in the newly formed epidermis of irradiated wounds compared with controls. Later, the epidermal expression of MMP1 in radiation wounds was comparatively increased following the delay of the healing process. (2) MMP1 expression in irradiated wounds was markedly decreased in fibroblasts, endothelial cells, and macrophages compared with controls. The expression phase was prolonged because of the delay of the healing process. The reduced expression of MMP1 in granulation tissue retards such important processes as cell migration, angiogenesis, and tissue remodeling, thus slowing the healing process. The expression ofMMPI in the proliferating keratinocytes may help re-epithelialization. However, in the late healing period, overexpression ofMMPI in the epidermis may hinder the establishment ofbasal membrane and the formation of granulation tissue, and affect the tissue remodeling process.
Detection of Human Papillomavirus DNA, Serum p53, and p53 Antibodies in Patients with Cervical Cancer
7
10.1615/JEnvironPatholToxicolOncol.v21.i1.80
Ranbir C.
Sobti
Department of Biotechnology, Panjab University, Chandigarh, India
Kamana
Parashar
Department of Biotechnology, Panjab University, Chandigarh, India
Raminder
Kaur
Department of Biotechnology, Panjab University, Chandigarh, India
Neena
Capalash
Department of Biotechnology, Panjab University, Chandigarh, India
Human papillomavirus (HPV) was detected in 85% and 63.6% of patients with invasive cervical cancer and minor cervical abnormalities, respectively. HPV-16 was the dominant type in both groups of women. Because of the high oncogenic potential of HPV-16 and the greater chance of its persistence, a follow-up of cases with minor cervical abnormalities harboring HPV-16 is warranted in order to observe the progression of the lesion. As many as 61.5% of the cases with invasive cervical cancer were found to have higher levels of serum p53 protein than did healthy controls. None of the patients had antibodies against the overexpressed p53. This suggests that, even if mutated, the p53 protein may not be immuno-genic in all cases. An inverse relationship between the presence of HPV and the alteration in p53 expression was observed in 71.43% of the cases. This could mean the loss of p53 function as a result of either HPV-E6-mediated degradation or mutation in the p53 gene.
The Effect of Recombinant Human Tumor Necrosis Factor-a on Ehrlich Ascites Tumor Growth
6
10.1615/JEnvironPatholToxicolOncol.v21.i1.90
Slawomir
Terlikowski
Department of Gynaecology and Septic Obstetrics, Medical Academy of Bialystok, Bialystok, Poland
Mariola
Sulkowska
Department of Pathological Anatomy, Medical Academy of Bialystok, Bialystok, Poland
Henryk F.
Nowak
Department of Pathological Anatomy, Medical Academy of Bialystok, ul. Waszyngtona 13, 15-269 Bialystok 8, Poland
We studied the antitumor effect of recombinant human tumor necrosis factor-a (rh TNF-a) on the intraperitoneal (i.p.) growth of Ehrlich ascites tumor (EAT) in Swiss albino male mice. The animals were treated with i.p. injection of rh TNF-a in doses of 5, 7.5, or 10 mg three times a week for 2 weeks, respectively, starting on the 4th day after the EAT inoculation. The effect of the cytokine was evaluated based on the following parameters: total ascites volume, packed cell volume, total packed cell volume, inhibitory growth rate, cellular population of EAT, morphological EAT cell changes, and mean survival time (MST). Rh TNF-a in a dose of 5 amg had only a slight effect on MST and inhibitory growth rate (IGR). After a dose of 7.5 mg, an increased IGR (p mg doses (p mg, a significant IGR (p p mg dose exerted a greater effect compared with the remaining doses, no complete regression was attained.