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PubMed1987

Monoclonal antibodies to ethanol-induced rat liver cytochrome P-450 that metabolizes aniline and nitrosamines.

Hybridomas were prepared from mouse myeloma cells and spleen cells derived from female BALB/c mice that had been immunized with a partially purified ethanol-induced rat liver cytochrome P-450 (P-450et). Monoclonal antibodies (MAbs) produced by the hybridomas were screened for binding to P-450et with a radioimmunoassay. Thirty-one independent hybrid clones produced MAbs that had a high affinity for P-450et. Each clone produced MAbs of a single subclass of the mouse immunoglobulins IgG1, IgG2a, IgM, or IgA. Ten of the 31 MAbs also immunoprecipitated P-450et as determined by Ouchterlony double-immunodiffusion analyses. One of the MAbs was tested for cross-reactivity with other rabbit and rat liver cytochromes P-450 and was found not to cross-react with rat liver P-450 induced by either phenobarbital, beta-naphthoflavone, or rabbit liver P-450LM2 or P-450LM4. Nine of the MAbs were tested for cross-reactivity with rat liver clofibrate-induced P-450, rat liver pregnenolone-16-alpha-carbonitrile-induced P-450, and a human liver P-450. All the MAbs showed no cross-reactivity except for one MAb which cross-reacted with both pregnenolone-16-alpha-carbonitrile and human P-450 and three MAbs which cross-reacted with human P-450. Three antigen-precipitating MAbs and four nonprecipitating MAbs were tested for their effects on the aniline p-hydroxylase activity of liver microsomes of untreated rats and from rats treated with acetone, pyrazole, methylpyrazole, or imidazole. One of the seven MAbs tested, 1-91-3, inhibited enzyme activity of acetone-, pyrazole-, or methylpyrazole-induced microsomes by 54, 47, and 48%, respectively. This indicates that at least 50% of microsomal cytochrome P-450 aniline p-hydroxylase activity in the latter is a function of a P-450 enzyme that contained the epitope to which the MAb 1-91-3 is directed. With untreated and imidazole-induced microsomes, 32 and 21% inhibition of the enzyme activity was observed. In reconstituted systems containing phospholipid and NADPH-cytochrome P-450 reductase, MAb 1-91-3 inhibited aniline p-hydroxylase activity of purified ethanol-induced P-450et and acetone-induced P-450 by more than 90%. Nitrosodimethylamine demethylase activity of acetone-induced rat microsomes was inhibited by the various MAbs up to 77% and the activity of the purified acetone-induced P-450 was inhibited up to 92%.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetone↗
PubMed1988

Detection in human cells of alkylated macromolecules attributable to exposure to nitrosamines.

Various methods for detecting DNA alkylation adducts are described briefly, with emphasis on immunoassays using antibodies against O6-methyldeoxyguanosine (O6-medGua), O4-methylthymidine (O4-meThy) and 7-methyldeoxyguanosine (7-medGua). The application of these methods to epidemiological studies is discussed, and results obtained so far on the presence of DNA alkylation adducts in human tissues are presented.

Alkylation↗
PubMed1987

N-nitrosamine formation by microorganisms isolated from human gastric juice and urine: biochemical studies on bacteria-catalysed nitrosation.

Twelve out of 14 bacterial strains isolated from patients with urinary infections and nine out of 30 microorganisms isolated from gastric juice from patients with gastric achlorhydria were shown to catalyse the formation of N-nitrosomorpholine (NMOR) from nitrite and morpholine at neutral pH. The effects of various metal ions and cofactors on the bacterial nitrosation reaction was investigated. The presence of nitrate in the culture medium was required to induce nitrosating activity in bacteria, but low nitrate concentrations inhibited the nitrosation reaction.

Escherichia coli↗
PubMed1988

Carcinogenicity of hydroxyalkylnitrosamines in F344 rats: contrasting behavior of beta- and gamma-hydroxylated nitrosamines.

The carcinogenicity of N-nitrosomethyl-(2-hydroxyethyl)amine (NMHEA), N-nitrosomethyl-(3-hydroxypropyl)amine (NMHPA), and the p-toluenesulfonate (tosylate) ester of NMHEA (NMHEATs) was tested in male and female F344 rats. The chemicals (25.6 mumol per application) were administered by twice-weekly gavage in corn oil (0.2 ml) for the lifetime of the animals. NMHEA was found to be an effective carcinogen under those conditions. The median survival time for the females was 9 mo after treatment was initiated, while for the males it was 12 mo. The principal cause of death of the females was hepatocellular carcinoma (14 of 20), while only 6 of 20 male rats exhibited that tumor. A few of the male rats had squamous cell carcinomas of the nasal epithelium (4 of 20), tumors which were not observed in the females. NMHPA was a much weaker carcinogen. Many of these rats survived for 2 yr and most had many age-related cancers. Nevertheless, 10 of the NMHPA-treated males and 2 females had adenocarcinoma of the lung, which was absent in the controls and also induced a significant number of neoplastic nodules in the livers of rats of both sexes. NMHEATs was also a weak carcinogen. However, besides many age-related tumors, it induced some hepatocellular carcinomas as well as hemangiosarcomas of the liver. NMHEATs was at least partially hydrolyzed to NMHEA, which was detected in the blood plasma of treated rats. A hypothesis has been advanced that NMHEA is activated to a proximate carcinogen by sulfate conjugation of the hydroxyl group; the present data do not contradict this hypothesis. The relatively lower carcinogenic potency of NMHPA, the different tumor spectrum induced by this chemical, and particularly the differences in chemical behavior suggest that its mode of activation is not the same as that for NMHEA.

Animals↗
PubMedDate not supplied

Nitrosamine carcinogen activation pathway determined by quantum chemical methods.

Multiple reactions are thought to be involved in transforming dialkynitrosamines to active carcinogens. The first proposed step is enzymatic alpha-hydroxylation by the active oxygen species of cytochrome P-450, followed by nonenzymatic N-dealkylation and formation of diazohydroxides (RNNOH). The latter transformation can reasonably occur by a two-step mechanism via tautomerization of a monoalkylnitrosamine intermediate or directly from the alpha-hydroxylated species in one step. Both of these pathways in the transformation of hydroxymethylnitrosamine to diazohydroxide and formaldehyde were examined by the semiempirical molecular orbital method MNDO (modified neglect of diatomic differential overlap) and the ab initio method using STO-3G and 3-21G basis sets. Complete geometry optimizations of all reactants, intermediates, transition states, and products were performed. MNDO was also used to compare the similar transformation of the dimethyl analog. Both methods show that in the gas phase a concerted pathway involving a six-membered ring transition-state pathway is kinetically favored over a two-step pathway involving N-demethylation followed by tautomerization via two four-membered ring transition states. This reaction appears to be a viable one to formation of an ultimate carcinogen by parent dialkylnitrosamines in the hydrophobic substrate binding site of cytochrome P-450.

Biotransformation↗
PubMed1986

Effects of dietary selenium on bis(2-oxopropyl)nitrosamine-induced carcinogenesis in Syrian golden hamsters.

In studies designed to determine the influence of dietary Se on pancreatic carcinogenesis, Syrian golden hamsters were fed unsupplemented torula yeast diet or diet supplemented with 0.1 or 5.0 ppm Se, from sodium selenite, starting at 4 weeks of age until the termination of the study. In separate groups, hamsters were given the diet supplemented with 0.1 ppm Se until 5 days after carcinogen treatment. Then they were fed either the unsupplemented diet or the diet supplemented with 5.0 ppm Se until the end of the experiment. N-Nitrosobis(2-oxopropyl)amine (BOP; CAS; 60599-38-4) treatment was given as a single sc injection of 20 mg/kg (body wt) at 8 weeks of age, and surviving hamsters were killed 50 weeks later. As a measure of Se status, glutathione peroxidase (GSHPX) activities were determined in plasma, erythrocytes, and liver. Values were elevated in animals fed higher levels of dietary Se. BOP treatment depressed plasma GSHPX at 24 hours and elevated erythrocyte and liver values at 4 weeks. Pancreatic ductular adenoma yields were inhibited with each elevation of dietary Se in female hamsters fed the diets, both before and after BOP administration, and were further inhibited in females that were fed diets containing 0.1 ppm Se before BOP administration and that were changed to the unsupplemented or 5.0-ppm-supplemented diets after BOP was given. Pancreatic ductular adenoma yields were highest in all male groups given diets of 0.1 ppm Se before BOP administration, irrespective of the Se level after BOP was fed. Adenoma yields in males were lowest in hamsters fed unsupplemented diet, both before and after BOP treatment. Pancreatic carcinoma yields were low and not influenced by dietary Se. The incidence of hepatic necrosis was elevated in BOP-treated hamsters fed the unsupplemented diet, and that of biliary cystic adenomas was highest in the group fed 0.1 ppm Se before and after BOP treatment.

Animals↗