Genetics of somatic mammalian cells. IX. Quantitation of mutagenesis by physical and chemical agents.
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Animals↗
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In the search for new anticancer drugs. XXII: Synthesis and anticancer evaluation of some dipeptides containing N-nitrosochloroethylamino and chloroethylamino moieties.
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Amino Acids↗
Ki-ras mutations in spontaneous and chemically induced renal tumors of the rat.
A high frequency of point mutations at codon 12 of the Ki-ras gene has previously been reported for rat kidney mesenchymal tumors induced by methylating N-nitroso compounds. In this study, we analyzed renal tumors with divergent histogenesis, i.e., mesenchymal tumors (sarcomas), cortical epithelial tumors (carcinomas), and embryonal tumors (nephroblastomas). Renal mesenchymal tumors and carcinomas were induced in juvenile or young adult Wistar rats by a single dose of N-nitrosodimethylamine (NDMA) while nephroblastomas were induced in Nb hooded rats by a single transplacental dose of N-nitrosoethylurea (NEU). Nephroblastomas developing spontaneously in WAB/Not rats were also examined. Amplification of Ki-ras sequences from formalin-fixed, paraffin-embedded tissue by the polymerase chain reaction was followed by direct DNA sequencing. GGT----GAT point mutations at codon 12 of the Ki-ras gene were found in 9 of 12 (75%) renal mesenchymal tumors and in 9 of 12 (75%) cortical epithelial tumors induced by NDMA. Even higher incidences were observed in nephroblastomas (8/8; 100%) induced by NEU and in spontaneous nephroblastomas (10/11; 91%). These results indicate that Ki-ras mutations are frequent events during the development of kidney tumors irrespective of their histogenesis and suggest that they may play an important role in renal carcinogenesis in rats. These data further indicate that mutational activation of Ki-ras proto-oncogenes in carcinogen-induced rat kidney tumors occurs in a tissue-specific, rather than cell-specific, manner.
Animals↗
Nitric oxide inhibits selectively the 17beta-estradiol-induced gene expression without affecting nongenomic events in HeLa cells.
17beta-Estradiol (E2) induces genomic (i.e., pC3-luciferase promoter-reporter construct expression) and nongenomic (i.e., DNA synthesis and IP(3) production) effects in HeLa cells only after transient transfection with the human estrogen receptor alpha (ERalpha) reporter plasmid. Here the effect of nitric oxide (NO) on both E2-induced effects in transiently transfected HeLa cells is reported. Remarkably, the E2-dependent gene transcription is inhibited dose-dependently by NO. By contrast, DNA synthesis and IP(3) production, representing nongenomic E2-dependent effects, are unaffected by NO. The selective NO action on E2-induced functions may be related to NO-mediated chemical modification(s) of the Cys residues present in the DNA recognition domain of ERalpha impairing DNA binding.
Aspartic Acid Endopeptidases↗
An ecologic study of nitrate in municipal drinking water and cancer incidence in Trnava District, Slovakia.
Contamination of drinking water by nitrate is an evolving public health concern since nitrate can undergo endogenous reduction to nitrite, and nitrosation of nitrites can form N-nitroso compounds, which are potent carcinogens. We conducted an ecologic study to determine whether nitrate levels in drinking water were correlated with non-Hodgkin lymphoma and cancers of the digestive and urinary tracts in an agricultural district (Trnava District; population 237,000) of the Slovak Republic. Routinely collected nitrate data (1975-1995) for villages using public water supplies were computerized, and each village was categorized into low (0-10 mg/L), medium (10.1-20 mg/L), or high (20.1-50 mg/L) average levels of total nitrate in drinking water. Observed cases of cancer in each of these villages were ascertained through the district cancer registry for the time period 1986-1995. Standardized incidence ratios (SIRs) and 95% confidence intervals (CI) for all cancer and selected cancer sites were calculated by indirect standardization using age- and sex-specific incidence rates from the entire district. For all cancer in women, SIRs increased from villages with low (SIR=0.87; 95% CI 0.72-0.95) to medium (SIR=1.07; 95% CI 1.00-1.13) to high (SIR=1.14; 1.06-1.22) levels of nitrate (P for trend <0.001); there was a similar trend for all cancer in men from low (SIR=0.90; 95% CI 0.81-0.99) to medium (SIR=1.08, 95% CI 1.02-1.16), but not for high (SIR=0.94; 0.88-1.02), nitrate levels (P for trend <0.001). This pattern in the SIRs (from low to high nitrate level) was also seen for stomach cancer in women (0.81, 0.94, 1.24; P for trend=0.10), colorectal cancer in women (0.64, 1.11, 1.29; P for trend <0.001) and men (0.77, 0.99, 1.07; P for trend=0.051), and non-Hodgkin lymphoma in women (0.45, 0.90, 1.35; P for trend=0.13) and men (0.25, 1.66, and 1.09; P for trend=0.017). There were no associations for kidney or bladder cancer. These ecologic data support the hypothesis that there is a positive association between nitrate in drinking water and non-Hodgkin lymphoma and colorectal cancer.
Digestive System Neoplasms↗
Percutaneous penetration of N-nitrosodiethanolamine through human skin (in vitro): comparison of finite and infinite dose applications from cosmetic vehicles.
N-Nitroso compounds (nitrosamines) have been detected at the parts per billion level in a wide variety of matrices including industrial chemicals, pharmaceuticals, and food. Although N-nitrosodiethanolamine (NDELA) may be detected as an impurity in some cosmetic products, studies on NDELA absorption through human skin have been limited. A study to determine the extent of NDELA absorption following topical application was therefore undertaken to assist in the proper assessment of risk following unintended exposure. NDELA absorption was measured in vitro through human cadaver skin using isopropyl myristate (IPM) and generic prototype personal-care formulations (sunscreen and shampoo) spiked with [14C]NDELA. When applied as a finite dose at a concentration of 0.06% or lower, NDELA absorption was found to be a linear function of concentration. Total absorption at 48 hr ranged from approximately 35 to 65% of the dose and was formulation dependent (IPM > shampoo > or = sunscreen). Absorption occurred relatively rapidly from all formulations and peak rates of absorption were seen within the first 5 hr from the IPM and shampoo formulations. When applied as an infinite dose, total NDELA absorption followed a different rank order (shampoo > or = IPM > sunscreen) and evidence of barrier damage was seen with the shampoo formulation.
Carcinogens↗
Evolution of differential substrate specificities in Mu class glutathione transferases probed by DNA shuffling.
A library of variant enzymes was created by combined shuffling of the DNA encoding the human Mu class glutathione transferases GST M1-1 and GST M2-2. The parental GSTs are 84 % sequence identical at the protein level, but their specific activities with the substrates aminochrome and 2-cyano-1,3-dimethyl-1-nitrosoguanidine (cyanoDMNG) differ by more than 100-fold. Aminochrome is of particular interest as an oxidation product of dopamine and of possible significance in the etiology of Parkinson's disease, and cyanoDMNG is a model for genotoxic and potentially carcinogenic nitroso compounds. GST M2-2 has at least two orders of magnitude higher catalytic activity with both of the substrates than any of the other known GSTs, including GST M1-1. The DNA library of variant Mu class GST sequences contained "mosaic" structures composed of alternating segments of both parental sequences. All clones contained the 5'-end of a GST M1-1 clone optimized for high-level expression in Escherichia coli. The remainder of the sequences derived from segments of GST M2-2 and GST M1-1 DNA. All of the clones analyzed contained between two and seven distinct DNA segments. In addition, each clone contained an average of approximately one point mutation. None of the library clones analyzed was identical with either of the two parental structures. Variant GST sequences were expressed in E. coli, and their enzymatic activities with aminochrome, cyanoDMNG, and 1-chloro-2,4-dinitrobenzene (CDNB) were determined in bacterial lysates. Such screening of more than 70 clones demonstrated a continuous range of activities covering at least two orders of magnitude for each of the substrates. For a given clone, the activities with aminochrome and cyanoDMNG, in spite of their different chemistries, were clearly correlated, whereas no strong correlation was found with CDNB. This functional correlation suggests a common structural basis for the enzymatic mechanisms for conjugation of aminochrome and denitrosation of cyanoDMNG. From an evolutionary perspective, the results show that recombination of segments from homologous proteins gives rise to a large proportion of functionally competent proteins with a range of activities. The data support the proposal that natural evolution of protein functions may involve recombination of DNA segments followed by selection for advantageous functional properties of the resulting proteins. Clearly, the same approach can be utilized in the engineering of proteins displaying novel functions by in vitro evolution.
Amino Acid Sequence↗
Chronic hepatitis C virus infection in humans: induction of hepatic nitric oxide synthase and proposed mechanisms for carcinogenesis.
Chronic inflammatory states frequently lead to the increased production of nitric oxide (NO) via inducible NO synthase (NOS-2). In addition, NO may produce mutagenesis through several mechanisms such as DNA oxidation, DNA deamination, and the formation of N-nitroso compounds. As there is a strong association between human hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC), we were interested in whether human HCV hepatitis leads to induction of NOS-2 and if the mutation repair system of p53/p21 was upregulated. Reverse transcriptase-polymerase chain reaction (RT-PCR) for human NOS-2 message was performed on RNA samples from both liver biopsies and whole liver from HCV-positive and control patients (normal liver from hepatic resections for metastases). Immunohistochemistry (IHC) for p53 and Western blot analysis for p21 were also performed on the whole liver samples. From the liver biopsies, 60% of HCV-positive patients expressed NOS-2 by RT-PCR. Looking at the whole liver samples, 100% of the HCV-positive patients expressed NOS-2 vs 12.5% in the normal samples. p53 was not detected in either group but there was upregulation of p21 over baseline expression in a number of the HCV-positive patients. Human HCV hepatitis leads to consistent upregulation of hepatic NOS-2 message, but message is not predictably present in "normal" human liver. There is also induction of p21 in some patients with HCV hepatitis. Chronic expression of NO in HCV hepatitis may play a role in DNA mutagenesis and the development of HCC.
Adult↗
Environmental and metabolic transformations of primary aromatic amines and related compounds.
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Amines↗
The role of chemical, physical, or viral exposures and health factors in neurocarcinogenesis: implications for epidemiologic studies of brain tumors.
This review highlights some future prospects and implications for epidemiologic research on the etiology of nervous system tumors. It reviews some points regarding physiology of the nervous system, in connection with mechanisms of neurocarcinogenesis, and experimental studies in animals. The results of epidemiologic studies are summarized in the light of the biological and experimental observations. The following aspects are particularly emphasized: (i) higher susceptibility of the developing nervous system to neurocarcinogenic agents (in the fetus and after birth); (ii) possible implications of knowledge about mechanisms of neurocarcinogenesis regarding crossing of the blood-brain barrier, activation of oncogenes and inactivation of anti-oncogenes, relationship between chemical structure and neurocarcinogenic action; (iii) necessity of further investigation concerning the occurrence of nitrosoureas and their precursors in the environment, and the potential role of nitroso compounds in the development of human brain tumors; (iv) lack of information about promoting or inhibiting neurocarcinogenic effects, and co-carcinogenesis--among others, interaction between X-irradiation and exposure to neurocarcinogenic nitrosoureas; (v) need for studying the potential neurocarcinogenic risk of polyomaviruses BKV, JCV, and SV40 to humans.
Animals↗
Mutagenicity of beta-oxidized N,N,-di-n-propylnitrosamine derivatives in S. typhimurium mediated by rat and hamster tissues.
The relative abilities of liver, kidney and lung fractions from untreated or phenobarbitone-pretreated rats and hamsters to convert N,N-di-n-propylnitrosamine and several beta-oxidized synthetic putative intermediates into mutagens was quantitatively compared in a tissue-mediated mutagenicity assay with S. typhimurium TA 1530 in vitro. With one exception, namely, N,N-di(2-acetoxy-n-propyl)nitrosamine, liver was the most active tissue from hamsters; in rats also, only liver fractions were able to activate some nitroso-compounds to mutagens. The highest enzyme-mediated mutagenicities were observed with N-2-hydroxy-n-propyl-N-n-propylnitrosamine, N,N-di-n-propylnitrosamine and N,N-di(2-acetoxy-n-propyl)nitrosamine. Hamster lung tissue converted N,N-di-n-propylnitrosamine, N-2-hydroxy-n-propyl-N-n-propylnitrosamine and N,N-di(2-acetoxy-n-propyl)nitrosamine into mutagens; activity with the latter compound was greater with lung tissue than with liver tissue when untreated animals were used. N-methyl-N-n-propylnitrosamine was mutagenic in the presence of hamster liver fraction but less so than N,N-di-n-propylnitrosamine. The results of the mutagenicity assays using various tissues are qualitatively compared to sites of tumour formation in rats and hamsters by these N-nitrosamines.
Animals↗
The oxidation of isomeric amino and acetamidobiphenyls by rat hepatic microsomal preparations.
The metabolism of isomeric amino and acetamidobiphenyls was studied using rat liver microsomal preparations. The aromatic amines were hydroxylated ortho or para to the amino group, whereas the aromatic amides were mainly oxidized in the para position. The carcinogenic amines 3- and 4- aminobiphenyl were converted to hydroxylamines and nitroso compounds. The non-carcinogenic amine 2-aminobiphenyl was resistant to enzymic nitrogen oxidation. The results support the concept that oxidation of aromatic amino groups is a prerequisite for carcinogenic and mutagenic activity.
Aminobiphenyl Compounds↗
Transaminase level (GOT, GPT) in rats under treatment with diethylnitrosamine.
Transaminase levels (GOT, GPT) of Sprague-Dawley-rats were not increased during long-term oral application of diethylnitrosamine (DENA) in doses of 0.1 and 3.0 mg/kg/day respectively. Only rise of the daily dose to 12.0 mg/kg/ (4% of LD50) resulted in a significant increase of enzymatic activities after 2-3 months of treatment. By the determination of transaminases the process of liver cancerization cannot be discovered. The present method is also too insensitive to indicate the formation of smaller quantities of nitroso compounds from their precursors (amines plus nitrite) in vivo.
Alanine Transaminase↗
[Change of toxicity and carcinogenicity of N-methyl-N-nitrosobenzylamine in rats by methylsubstitution in the phenylresidue].
Substitution with a methyl group in the 2-, 3- or 4-position respectively of the phenyl moiety of N-methyl-N-nitrosobenzylamine results in a considerable reduction of the acute toxicity. (LD 50 of MNBA: 18 mg/kg (Druckrey et al., 1967), 2-Me-MNBA: 90 mg/kg, 3-Me-MNBA: 600 mg/kg, 4-Me-MNBA: 400 mg/kg). However, the introduction of the methyl group influences the carcinogenic activity of MNBA in rats and its organotropy, only to a small extent. Long-term administration of 5 and 15 ppm respectively of the isomeric N-nitroso compounds in the drinking water produces in all animals carcinomas of the oesophagus and the pharynx.
Animals↗
Effect of N-nitrosamines carcinogenic for oesophagus on O6-alkyl-guanine-DNA-methyl transferase in rat oesophagus and liver.
Several O6-alkylGua adducts have been shown to be removed from DNA during its repair by transfer of the alkyl group to a cysteine residue in a specific AAP, with the formation of S-alkylcysteine. As the reaction is stoichiometric and irreversible, the AAP content of the cell can be reduced or depleted. In vivo depletion by a high dose of nitrosamine can be used to test for the formation of a repairable alkylation adduct at the O6-position of guanine. In addition, if the carcinogenic potency of a nitroso compound for a particular organ is related to the persistence of the adduct in DNA, potency would depend not on the level of alkylation attained after treatment, but on whether this was sufficient to deplete the AAP content of the organ concerned and so to slow down repair, i.e. depletion of AAP is a more relevant estimate of potency than is the initial extent of DNA alkylation. Dose-response studies on target and non-target organs showed that depletion of AAP correlated with organotropy for those nitrosamines known to methylate DNA, i.e. with NDMA for liver, and with NMBzA for oesophagus. With NDEA, the results supported the suggestion that other adducts in addition to O6-alkylGua may be involved. NMPhA, an oesophageal specific carcinogen, did not deplete AAP in oesophagus, and induced AAP in liver. This result adds to the evidence that NMPhA does not alkylate DNA.
Alkylation↗
DNA adducts in experimental cancer research.
The role of DNA adducts in the initiation of cancer is scrutinized in this presentation. Work on the activation of oncogenes, particularly on ras, has provided new evidence to link DNA adducts and tumour formation. Polycyclic hydrocarbons and nitroso compounds can cause activation of ras oncogenes through a defined point mutation. The properties of two DNA binding agents, styrene oxide and cisplatin are discussed. Styrene oxide is a versatile electrophile causing numerous adducts; cisplatin has a high specificity towards guanine-N-7 and cross-link formation. Finally, the relation of specific adducts to carcinogenic potency as defined by TD50 values is investigated. For small alkyl groups, O-alkylation of bases correlates with potency but among others, particularly the bulky carcinogens, 7-alkylguanines appear as correlates of potency. Most such potent agents forming 7-alkylguanines induce depurination and imidazole ring-opening.
Alkylation↗
Induction of tumors in the small intestine and mammary gland of female Donryu rats by continuous oral administration of N-carboxymethyl-N-nitrosourea.
The carcinogenicity of N-carboxymethyl-N-nitrosourea (CMNU), a naturally occurring N-nitroso compound, was tested in female Donryu rats. Four groups of female Donryu rats were given 400, 200, 100, or 0 ppm of CMNU solution continuously as drinking water. The incidence of tumors was highest and the mean survival time shortest in the 400 ppm group. A dose-effect relationship was observed in the tumor incidence and the mean survival time and the incidences of tumors in all experimental groups were significantly different from those in the control group. In the 400 ppm group, tumors were detected most frequently in the small intestine, followed by the mammary gland. In contrast, most tumors were observed in the mammary gland in the other two experimental groups, although dose-dependent induction of tumors of the small intestine was also detected in these two groups. The organ specificity of CMNU is compared with that of other N-alkyl-N-nitrosourea derivatives.
Animals↗
Betel nut (Areca catechu) consumption and the induction of glucose intolerance in adult CD1 mice and in their F1 and F2 offspring.
Many mutagenic nitroso compounds are also diabetogenic. Betel-nut (Areca catechu) chewing populations have an increased incidence of foregut cancers related to betel-nut nitrosamines which suggests that betel consumption could be diabetogenic. Young adult CD1 mice with a low spontaneous incidence of diabetes were fed betel nut in standard feed for 2-6 days. Single point (90 min) intra-peritoneal glucose tolerance tests were used to follow glucose tolerance up to 6 months of age. Glucose intolerance was defined as over 3 SD above mean control values. Glucose intolerance was found in 3 of 51 male and 4 of 33 female adult mice which were fed the betel diet (p < 0.01). Studies on the progeny of these mice are presented separately for animals studied in Aberdeen (Group 1) and London (Group 2). In matings of Group 1 betel-fed parents glucose intolerance was found in 4 of 25 male and 1 of 22 female F1 offspring, with significant hyperglycaemia in F1 males born to hyperglycaemic but not to normoglycaemic mothers (p < 0.01). In the F2 generation 4 of 23 males and 1 of 16 females and in the F3 generation 1 of 16 males and 0 of 20 females were glucose intolerant. In the Group 2 studies where betel-fed parents were mated to normal controls glucose intolerance was found in 10 of 35 male and 10 of 33 female F1 progeny (p < 0.005), and mean islet areas were increased in offspring of betel-fed parents (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗