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PubMed1994

Recovery of dimethylnitrosamine-induced immunosuppression by pargyline in the mixed cultures of murine hepatocytes and splenocytes.

To investigate the role of monoamine oxidase (MAO) in dimethylnitrosamine (DMN)-induced suppression of the antibody response to sheep erythrocytes, the effect of an MAO inhibitor, pargyline, was studied in mixed cultures of murine hepatocytes and splenocytes. When pargyline was added simultaneously with DMN during the coculture, DMN-induced immunosuppression was clearly recovered dose-dependently. Cyclophosphamide was used as a comparative control in these studies. Surprisingly, pargyline also reversed cyclophosphamide-induced suppression of the antibody response in the coculture system. The results with cyclophosphamide were not consistent with a role by MAO, and suggested that pargyline may not be selective for MAO. To confirm our hypothesis, the ability of pargyline to inhibit three cytochrome P-450 (P-450) isozyme-specific monooxygenase activities in vitro was studied using mouse liver microsomes. Pargyline, under the same concentration ranges that we used in the coculture studies, clearly inhibited the P-450IIE1-specific p-nitrophenol hydroxylase activity and P-450IIB1-specific pentoxyresorufin O-dealkylase activity. Taken together, our present results indicate that pargyline inhibits P-450 activity and is not selective for MAO. Although further studies are required to confirm a possible role by MAO in DMN-induced immunosuppression, our results suggest that pargyline may recover DMN-induced immunosuppression by primarily inhibiting the ability of P-450 enzymes in hepatocytes to activate DMN to its immunosuppressive metabolite(s).

Animals↗
PubMed1975

The lethal effect on bacteria of dimethylnitrosamine used without an activating agent.

Survival curves have been obtained for various strains of bacteria treated with dimethylnitrosamine (DMN) solutions of different concentrations. The results are compatible with the conclusion that DMN kills the bacteria by an attack on their deoxyribonucleic acid (DNA) and the damage so caused can be repaired by the same systems that repair damage created by ultraviolet light or X radiation. No activating agent was added to the DMN solutions and under these circumstances their activities were in proportion to the squares of their concentrations. It is suggested that this is because two molecules of DMN plus one of oxygen produce two carbonium ions, two hydroxyl ions, two formaldehyde molecules and two nitrogen molecules.

DNA Repair↗
PubMed1975

In vitro metabolic activation of chemical mutagens. I. Development of an in vitro mutagenicity assay using liver microsomal enzymes for the activation of dimethylnitrosamine to a mutagen.

Qualitative and quantitative assays were developed to study the in vitro enzymatic activation of dimethylnitrosamine (DMNA) to its mutagenic form. Three different fractions from mouse liver homogenates, including purified microsomes, were employed for the activation, and several parameters of the assays were investigated. Qualitative tests were conducted to measure the ability of hepatic enzymes obtained from six mammalian species to activate DMNA. A comparison between two inbred mouse strains using the in vitro activation assay demonstrated that this technique might be a useful tool in quantitatively measuring differences in genetically influenced levels of DMNA metabolism in individuals animals and their tissues.

Animals↗
PubMed1976

The utilization of in vitro mutagenesis techniques to explain strain, age and sex related differences in dimethylnitrosamine tumor susceptibilities in mice.

The carcinogen dimethylnitrosamine (DMNA) is known to exhibit a high degree of strain, organ, age, and sex related tumor specificity in mice. Using microbial mutagenesis assay coupled with mouse tissue microsomal enzyme activation systems, evidence has been obtained that demonstrated a close relationship between the level of in vitro DMNA activation to a mutagen and in vivo tumor susceptibility. DMNA activation by liver, lung, and kidney microsomes from several mouse strains was compared by measuring the rate of mutagenic metabolites formed during incubation of the carcinogen in mutation assays using Salmonella typhimurium G-46 as the indicator microorganism.

Age Factors↗
PubMed1978

Mutagenicity of dimethylnitrosamine and ethyl methanesulfonate as determined by the host-mediated CHO/HGPRT assay.

Host-mediated assays have been developed to allow determination of the mutagenic potential of promutagens and procarcinogens which require metabolic activation to exert their effects on indicator organisms. We report here the development of the host-(mouse)-mediated CHO/HGPRT system using the procarcinogen dimethylnitrosamine (DMN) as a model agent. Using a 2--h treatment time, we observed a linear dose-response relationship up to 250 mg of DMN per kg body weight. At 100 and 500 mg/kg DMN, mutation induction increased with time up to at least 6 h. DMN was not mutagenic when tested in vitro. Athymic (nude) mice, their phenotypically normal littermates, or BALB/c mice of both sexes were found to be suitable as hosts. A time- and dose-dependency of induced mutation frequency by a direct-acting agent, ethyl methanesulfonate (EMS), was observed in both the in vitro and the host-mediated assays.

Animals↗
PubMed1981

Effect of calcium phosphate and alumina C gamma gels on the mutagenicity and cytotoxicity of dimethylnitrosamine as studied in the CHO/HGPRT system.

When CaCl2 was added in increasing concentrations to a rat liver metabolic activation system (S9) buffered with sodium phosphate, the mutagenic activity and cytotoxicity of dimethylnitrosamine (DMN) in the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyl transferase (CHO/HGPRT) system were greatly increased. This effect was not observed with an S9 mix buffered with N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). The calcium phosphate gel precipitate of the S9 mix possessed approximately 1/3 of the total activity of the mix, while the supernatant had only slight activity. However, when the calcium phosphate gel precipitate of a solution of S9 salts (without S9 protein) was added to the supernatant, the remaining 2/3 of the activity was recovered. Commercially obtained calcium phosphate, tricalcium phosphate, and alumina C gamma gels could substitute for CaCl2 in the S9 mix, but diethylaminoethyl cellulose (DEAE cellulose) could not. Alumina C gamma gel can exert its effect in the absence of both CaCl2 and phosphate in the S9 mix. Increasing the time of contact between the S9 protein and the S9 salts increased the efficacy with which the S9 mix activated DMN; this is indicative of an adsorptive process by calcium phosphate gel.

Alum Compounds↗
PubMed1982

Relation between the somatic toxicity of dimethylnitrosamine and a genetically determined variation in the level and induction of cytochrome P450 in Drosophila melanogaster.

The insecticide-resistant Drosophila strain Hikone R differs genetically from sensitive strains by having a higher activity of cytochrome P450 and a lack of inducibility with phenobarbital. Toxicity tests with dimethylnitrosamine (DMN) showed that: (a) the toxic effect of DMN was higher in the insecticide-resistant strain than in sensitive strains in accord with data by Vogel (1980); and (b) induction with phenobarbital increased the toxicity of DMN in the sensitive strains but not in the resistant strain. A dominant gene, responsible for the metabolic pattern of Hikone R and the non-inducibility, was located to 66 cM, near the gene vg in chromosome 2. This gene is most likely identical with that causing insecticide resistance, described by Kikkawa (1961).

Animals↗
PubMed1982

Metabolic activation of benzo[a]pyrene, aflatoxin B1, and dimethylnitrosamine by a human hepatoma cell line.

The metabolism of chemical carcinogens by a human hepatoma cell line, huH-1, was studied. The huH-1 line has been derived from a hepatoma of a 57-year-old HBs-antigen carrier and cultivated for several years. The hepatoma cells metabolized about 90% of 5 microM benzo[a]pyrene into water-soluble products within 24 h. Aryl hydrocarbon hydroxylase activity in huH-1 cells was induced to 24 times higher than the basal level by treatment with 13 microM benz[a]anthracene for 24 h. Metabolic activation of benzo[a]pyrene, dimethylnitrosamine and aflatoxin B1 by huH-1 cells was observed by cell-mediated sister-chromatid exchange assay. Sister-chromatid exchanges in human diploid fibroblasts were observed in the cultures mixed with or without huH-1 cells. All 3 chemicals induced sister-chromatid exchanges in human fibroblasts far more efficiently in the cultures mixed with huH-1 cells than in those without huH-1 cells. Some characteristics of huH-1 cells as a human cell-mediated metabolic activation system for carcinogens are discussed.

Aflatoxin B1↗
PubMed1983

The induction of chromosomal damage in rat hepatocytes and lymphocytes. I. Time-dependent changes of the clastogenic effects of diethylnitrosamine, dimethylnitrosamine and ethyl methanesulfonate.

Male Wistar rats received a single injection of diethylnitrosamine (DEN), dimethylnitrosamine (DMN) or ethyl methanesulfonate (EMS). After a number of time intervals (up to 56 days) liver cells were assayed for the presence of possible preclastogenic damage by performing partial hepatectomy and subsequent analysis of chromosomal damage (micronucleus formation) in isolated hepatocytes. Peripheral blood lymphocytes from the same animals were collected, stimulated to proliferate and assayed for the frequency of sister-chromatid exchanges (SCEs). Whereas all agents significantly increased frequencies of SCEs in lymphocytes up to at least 28 days (EMS) or 56 days (DMN, DEN) after injection, only the latter 2 compounds gave rise to significantly increased incidences of micronucleated hepatocytes. DMN-induced preclastogenic damage in hepatocytes was lost between 28 and 56 days after injection. After DEN, this type of damage was persistent over the entire experimental period (56 days). When rats treated with DEN did not undergo partial hepatectomy, the frequencies of micronuclei at different time intervals after treatment were at control level. This result, together with those from hepatectomized DEN-treated rats, suggests that it is the persistent character of the preclastogenic damage that is responsible for the occurrence of micronucleated hepatocytes at later time intervals after treatment with DEN, rather than the stability of micronuclei which might eventually have been formed soon after injection.

Animals↗
PubMed1983

The induction of chromosomal damage in rat hepatocytes and lymphocytes. II. Alkylation damage and repair of rat-liver DNA after diethylnitrosamine, dimethylnitrosamine and ethyl methanesulphonate in relation to clastogenic effects.

Rat-liver DNA alkylation by diethylnitrosamine (DEN), dimethylnitrosamine (DMN) and ethyl methanesulphonate (EMS) was studied in an attempt to relate chromosome-damaging effects of these agents (the formation of micronuclei in hepatocytes; see preceding paper) to specific alkylation patterns. No correlation was observed between the induction of micronuclei and liver DNA N-alkylation, measured as 3- and 7-alkyl-purines. O6-Alkylguanine is probably not involved in micronucleus induction because it is lost from DNA too rapidly to explain the much more persistent clastogenic effects. In contrast, both the initial amounts of alkylphosphotriesters and the persistencies of these products roughly paralleled the respective effects on micronucleus induction. The possible involvement of alkylphosphotriesters or other O-alkylation products of comparable stabilities is discussed. Results with DMN suggest that part of the primary DNA methylation damage is converted into a secondary (DNA) lesion and that both the primary and secondary lesion(s) contribute to the process of micronucleus formation.

Alkylation↗
PubMed1984

Dietary selenium deficiency causes decreased N-oxygenation of N,N-dimethylaniline and increased mutagenicity of dimethylnitrosamine in the isolated rat liver/cell culture system.

Male Wistar rats were fed diets of varying selenium content in order to obtain selenium-deficient and selenium-supplemented rats. After 5-6 weeks on the respective diet, the rats were used to investigate how selenium influences the effect of dimethylnitrosamine (DMN) on some liver enzymes and related reactions. The selenium-dependent glutathione peroxidase activity in postmicrosomal supernatant from liver was about 1% in selenium-deficient rats as compared to selenium-supplemented rats or rats fed a standard diet. The highest DMN-demethylase activity was observed in postmitochondrial supernatant from selenium-deficient rat liver, and the lowest in selenium-supplemented rats. No dietary effect was observed on hepatic microsomal cytochrome P450 levels. C-Oxygenation of N,N-dimethylaniline (DMA) was not affected by the selenium level. On the other hand, selenium deficiency seemed to reduce N-oxygenation of DMA. The mutagenicity of DMN in Chinese hamster V79 cells after metabolic activation by the isolated perfused rat liver, was approximately doubled when selenium-deficient livers were used as compared to selenium-supplemented livers and livers from rats fed a standard diet. A negative correlation between DMA-N-oxygenation and mutagenicity from DMN was observed, whereas no correlation between DMA-C-oxygenation and mutagenicity from DMN was found.

Aniline Compounds↗
PubMed1986

Rat and hamster hepatocyte-mediated induction of SCEs and mutation in V79 cells and mutation of salmonella by aminofluorene and dimethylnitrosamine.

Aminofluorene (AF) and dimethylnitrosamine (DMN) were examined for their ability to induce multiple genetic endpoints after rat and hamster hepatocyte metabolic activation. The endpoints measured included mutations at the Na+/K+-ATPase (ouabain resistance) and hypoxanthine-guanine-phosphoribosyltransferase (6-thioguanine resistance) loci, and sister-chromatid exchanges (SCEs) in Chinese hamster V79 cells, and mutation of Salmonella typhimurium strains TA98 and TA100. AF, with rat and hamster hepatocyte activation, induced only low levels of mutations at either loci in V79 cells but did induce SCEs. Mutation of Salmonella by AF after hepatocyte activation also occurred and was a sensitive endpoint for detecting this aromatic amine. DMN induced high levels of mutations at both loci in V79 cells in addition to SCEs in the presence of hepatocytes from both species. DMN was also mutagenic to Salmonella, but only with hamster hepatocytes. Salmonella did not respond as strongly to DMN as the V70 cells. Hamster hepatocytes were more active than rat hepatocytes in activating both carcinogens. The results indicate the variable sensitivity of the genetic endpoints and species differences in activation for two potent chemical carcinogens.

Animals↗
PubMed1989

Production of DNA single-strand breaks in unstimulated splenocytes by dimethylnitrosamine.

In an attempt to elucidate the mechanism whereby primary hepatocytes, but not liver S9 homogenates, generate immunosupprssive metabolites of dimethylnitrosamine (DMN), the production of DNA single-strand breaks (SSB) in unstimulated splenocytes was investigated with alkaline-elution analysis. Both hepatocytes and S9 homogenates induced SSB in cultured splenocytes by DMN - minimum detectable doses with the two metabolic activation systems (MAS) were 1 microM and 5 mM, respectively. DNA elution profiles were linear in splenocytes co-cultured with DMN and hepatocytes and convex in splenocytes incubated with DMN and S9 homogenates. Aminoacetonitrile (AAN; 10 mM), a DMN demethylase inhibitor, reversed SSB in splenocytes when incubated with either MAS. Addition of exogenous calf-thymus DNA to the hepatocyte co-culture medium did not affect the production of SSB. Rocking the hepatocyte-splenocyte cultures changed the elution profile from linear to convex. All of these treatments have been previously shown to block the immunosuppression by DMN in the hepatocyte co-culture system. These results indicate that the immunosuppression by DMN is not related to DNA damage, as measured by the production of SSB, and suggest that the metabolism of DMN to intermediates capable of producing genotoxicity and immunotoxicity may be qualitatively and/or quantitatively different.

Acetonitriles↗
PubMed1993

Ability of N-methyl-N'-nitro-N-nitrosoguanidine, 4-nitroquinoline 1-oxide, dimethylnitrosamine, and NaCl to induce unscheduled DNA synthesis, stimulate replicative DNA synthesis, and produce DNA single-strand breaks in pyloric mucosa of rat stomach.

Male F344 rats were given test chemicals orally, and samples of their pyloric mucosa were incubated in vitro. Induction of unscheduled DNA synthesis (UDS) and stimulation of replicative DNA synthesis in the pyloric mucosa were then examined by addition of [3H]thymidine and simultaneous determinations of DNA synthesis in the presence and absence of hydroxyurea, an inhibitor of replicative DNA synthesis. DNA damage was also examined by the alkaline elution method with DNA single-strand scission as a marker. The results showed four types of abilities of the chemicals to affect UDS and replicative DNA synthesis in the pyloric mucosa of rat stomach 1-2 h after their administration: (1) induction of UDS and stimulation of replicative DNA synthesis by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a glandular stomach carcinogen, (2) induction of only UDS by 4-nitroquinoline 1-oxide (4NQO), a glandular stomach carcinogen, (3) stimulation of only replicative DNA synthesis by NaCl, a glandular stomach tumor promoter, and (4) neither induction of UDS nor stimulation of replicative DNA synthesis by dimethylnitrosamine (DMN), a liver carcinogen. DNA single-strand scission was induced by MNNG and 4NQO, being maximal 2 h after their administration, but was not induced by NaCl or DMN. Thus it correlated well with the induction of UDS. The present results indicate four types of inductive abilities of chemicals on UDS and replicative DNA synthesis in rat stomach pyloric mucosa and show that this method can detect differences in the action mechanisms and organ specificities of glandular stomach carcinogens.

4-Nitroquinoline-1-oxide↗
PubMed1984

Hepatic transport of indocyanine green in dogs chronically intoxicated with dimethylnitrosamine.

Hepatic transport of indocyanine green (ICG) was examined in dogs chronically intoxicated with dimethylnitrosamine (DMN) (2 mg/kg) intraportally once a week for 6 weeks. In pathophysiological consequences, significant increases (p less than 0.05) were shown in both glutamic-pyruvic transaminase (GPT) and total plasma bile acids, but no significant difference was shown in body weight, liver wet weight, glutamic-oxaloacetic transaminase (GOT), plasma alkaline phosphatase activity, total plasma protein, and total plasma bilirubin. By histologic examination of livers from intoxicated dogs, increased fibrosis in periportal, perisinusoidal, and especially pericentral areas, with loss of normal architecture, was observed. Partial fibrous bridging between periportal and pericentral areas was also demonstrated, but extensive pseudolobulation with regenerative nodules was not observed. The portal venous pressure of the intoxicated dogs was increased by approximately 50% of that of control dogs. In intoxicated dogs, delays were shown in both plasma disappearance and biliary excretion of ICG and significant decreases were observed in the pharmacokinetic parameters k12 (plasma to liver transfer rate constant), V2 (distribution volume of liver compartment), and CLtot (total body-plasma clearance), while a significant increase was observed in k23 (intrahepatic diffusion and transport rate constant); the V1 (distribution volume of plasma compartment) was not altered. From these findings, it is suggested that the decrease in the intrinsic clearance of ICG for the hepatic uptake process might explain the decrease in ICG uptake rate into the liver which was observed in the DMN-intoxicated dogs. Dogs chronically intoxicated with DMN might be a good model for studying hepatic dysfunction.

Alanine Transaminase↗
PubMed1985

The effect of dimethylnitrosamine on host resistance and immunity.

Adult female B6C3F1 mice were injected ip with 0.2 ml phosphate-buffered saline (PBS) only or PBS containing 1.5, 3, or 5 mg dimethylnitrosamine (DMN)/kg body wt daily for 14 days. On Day 16, mice were evaluated for changes in immune status as measured by the antibody response to sheep red blood cells (SRBCs), blastogenesis to T- and B-cell mitogens, natural killer (NK) cell function, delayed hypersensitivity, and alveolar macrophage (AM) bactericidal activity; and for changes in host resistance following challenge with various microorganisms or tumor cells. DMN-exposed animals exhibited reduced humoral antibody responses, T-cell mitogenesis, and AM bactericidal activity. B-cell mitogenesis, NK cell activity, and delayed hypersensitivity were increased. Resistance to challenge with Listeria monocytogenes, Trichinella spiralis, or Herpes simplex types 1 or 2 virus (HSV-1, HSV-2) was not significantly impaired, while that to Streptococcus zooepidemicus and influenza virus was significantly reduced. Resistance to B16-F10 tumor challenge was enhanced following DMN exposure. The data show that DMN treatment altered humoral immunity and antibody-mediated host defense mechanisms. Increased NK cell activity may account for the increased resistance to challenge with Herpes virus and B16-F10 tumor cells.

Animals↗
PubMed1987

Suppression of in vitro antibody production by dimethylnitrosamine in mixed cultures of mouse primary hepatocytes and mouse splenocytes.

The suppression of in vitro antibody responses by dimethylnitrosamine (DMN) was produced in a mouse hepatocyte and splenocyte co-culture system. Mouse hepatocytes were isolated from female B6C3F1 mice and cultured for 20-24 hr to allow the formation of a monolayer on collagen-coated plastic petri dishes. Spleen cells were isolated from the same hybrid and were co-cultured with the hepatocytes along with DMN. Cyclophosphamide (CP), an immunosuppressive agent requiring metabolic activation that was included as an initial positive control, produced a marked suppression of the in vitro antibody responses to LPS, DNP-Ficoll, and SRBCs in 4 hr in the co-culture system. Under comparable conditions DMN markedly suppressed the response to SRBCs, marginally suppressed the response to DNP-Ficoll, and did not suppress the polyclonal response to LPS. The suppression by DMN was related to the rocking speed during the 4-hr co-culture period and was optimally produced when the cultures were not rocked. Addition of serum into the medium (10% fetal calf serum) during the co-culture period did not change the effects of DMN on the antibody response. However, the addition of extracellular DNA (1 mg calf thymus DNA/ml) prevented the suppression of the antibody response by DMN. These results suggest that DNA represents the primary macromolecular target for the reactive intermediate of DMN, and indicate that a syngeneic co-culture system can be used to characterize the in vitro immunosuppression

Animals↗
PubMed1992

Dimethylnitrosamine (DMN)-induced IL-1 beta, TNF-alpha, and IL-6 inflammatory cytokine expression.

Altered immune functions have been demonstrated in mice following exposure to dimethylnitrosamine (DMN). In particular, changes in cell-mediated immune responses resulted from chronic DMN exposure in vivo. Since cytokines are potent immunoregulatory peptides, experiments were performed to determine whether DMN exposure results in the induction of serum-borne inflammatory cytokines. Animals were exposed to either vehicle (PBS) or DMN (5.0 mg/kg) every 24 hr for 14 days. Serum and liver samples were obtained from individual mice at 0, 1, 2, 3, 6, 12, and 24 hr following the first exposure, with additional samples collected every 24 hr preceding the daily DMN exposure. Sera were then analyzed for IL-1 beta, IL-3, IL-6, CSF-1, GM-CSF, and TNF-alpha activities using either biological or immunological assays. In addition, liver total cellular RNA was probed for the induction of IL-1 beta transcripts using the solution hybridization/RNase protection assay. IL-1 beta, IL-6, and TNF-alpha serum activities were observed within 2 hr of DMN exposure and returned to vehicle control levels by 3 days even though DMN exposure was maintained. Chronic expression of cytokine activity (after 72 hr) was only observed for GM-CSF. A rapid induction of IL-1 beta transcripts (within 1 hr) in both vehicle and DMN-treated animals was observed by solution hybridization. However, by 3 hr postexposure, transcript levels decreased in the vehicle-treated animals while remaining elevated in the DMN-treated animals for 6 hr. These results demonstrated that DMN exposure in vivo induced: (1) the expression of serum-borne cytokine activities, and (2) IL-1 beta transcription in liver tissue.

Animals↗