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M C Archer

Publications and source records attributed to M C Archer.

At least 91 records · Page 5Linked to original sources
PubMed1984

Catalysis and inhibition of N-nitrosation reactions.

A number of factors that can lead to an acceleration or inhibition of N-nitrosation reactions may play an important role in the formation of N-nitroso compounds in foods and other environmental samples and in the body. The anion thiocyanate is a particularly effective catalyst for nitrosamine formation. It occurs in normal human saliva, but at higher concentrations in the saliva of smokers. Although nitrosation reactions are accelerated in the normal manner with increasing temperature, rate enhancements are also observed in frozen systems, a phenomenon that may be important in frozen foods. Surfactants that form micellar aggregates can accelerate the nitrosation of hydrophobic amines. This may be important in foods in view of the presence of components such as lecithin, or in the body in view of the occurrence of bile acid micelles. Nitrosation reactions may also be accelerated in the presence of certain carbonyl compounds, thiols and nitrosophenols. A number of compounds readily convert nitrosating agents into innocuous products and hence inhibit nitrosation reactions. If reductones such as ascorbic acid are present, they may react much faster with nitrous acid than amines and therefore effectively scavenge the nitrosating agent. Rapid reaction of polyhydroxyphenols with nitrous acid is another example of how endogenous or exogenous nitrosation reactions may be inhibited. Many microorganisms can influence nitrosation reactions by converting nitrate to nitrite, a reaction that can take place in foods, but which is particularly important in the body.

Ascorbic Acid↗
PubMed1984

Oxidation of ammonia and hydroxylamine to nitrate in the rat.

We have demonstrated that ammonia is oxidized to nitrate in the rat. Male Sprague-Dawley rats gavaged with 1 000 mumol 15N-ammonium chloride each day for five days were found to excrete low, but significant, amounts of excess 15N-nitrate in their urines on the five days of treatment and on the five subsequent days. We recovered a total of 0.28 +/- 0.03 mumol excess 15N-nitrate (mean +/- SE) per rat, which indicates that ammonia is converted to nitrate with a yield of about 0.0080%. 15N-Hydroxylamine was oxidized in the rat to 15N-nitrate with a yield of 4.7%, but oxidation of 15N-labeled glycine and L-glutamic acid to 15N-nitrate could not be detected. These results suggest that hydroxylamine, but not glycine or L-glutamic acid, may be an intermediate in the ammonia oxidation process. The injection of rats with Arochlor 1254 failed to stimulate nitrate synthesis, which indicates that the cytochrome P-450 drug metabolizing system is probably not involved in ammonia oxidation. Carbon tetrachloride, which causes hepatic lipid peroxidation, produced a small, but significant, increase in nitrate synthesis. Our results are consistent with the hypothesis that ammonia is oxidized in vivo by a non-enzymatic process involving reactive oxygen species. We estimate that a 215 g rat produces 3.0 mumol of nitrate per day by this process. The significance of our results to the problem of endogenous N-nitroso compound formation in man is discussed.

Ammonium Chloride↗
PubMed1984

Tissue and species specificity of the microsomal metabolism of N-nitrosomethylbenzylamine.

The microsomal activation of N-nitrosomethylbenzylamine (NMBzA) by oxidation at the methylene carbon atom was examined in various organs of a number of species to determine the role of metabolism in the organ-specificity of tumour induction by NMBzA. In Sprague-Dawley rats, NMBzA was metabolized by microsomes from liver, lung and oesophageal mucosa. In Fischer F-344 rats and in rabbits, metabolic activity was present in both liver and oesophageal mucosa, the only tissues studied in those species. In contrast, in Syrian hamsters and in BALB/cBYJ mice, no NMBzA metabolism was detectable in the oesophagus, but it occurred at relatively high rates in liver, lung and kidney. The forestomach mucosa exhibited undetectable levels of activity in all species except the hamster in which it was present at a very low level. In human oesophageal mucosal microsomes from six patients, rates of metabolism of NMBzA were either undetectable or approximately 70 times lower than those in the Sprague-Dawley rats. A comparison of NMBzA metabolism in the different species with the known carcinogenicity of the nitrosamine in rats and rabbits, and our preliminary data on the acute toxicity of NMBzA in hamsters and mice suggests that, in the oesophagus at least, metabolic activation of NMBzA is necessary to elicit its toxic and/or carcinogenic effect. However, in the liver, which in all species has high metabolic activity but which is also resistant to the toxic and carcinogenic effects of NMBzA, other factors besides metabolic activation must be involved.

Animals↗
PubMed1984

Increased endogenous nitrosation in smokers.

Endogenous nitrosation of proline was investigated in smokers and nonsmokers. Volunteers consumed a volume of beetroot juice equivalent to 325 mg nitrate and, 1 h later, 500 mg proline. In separate experiments, volunteers ingested proline alone. Twenty-four-hour urines were collected and analysed for N-nitrosoproline. When proline was ingested alone, there was no significant difference in urinary N-nitrosoproline excretion between smokers and nonsmokers. When beetroot juice and proline were consumed, however, smokers produced approximately 2.5 times as much N-nitrosoproline as nonsmokers. Salivary nitrite levels of smokers and nonsmokers, both before and after consumption of beetroot juice, were not significantly different. Salivary thiocyanate levels were approximately 3.2. times higher in smokers than in nonsmokers. Our results suggest that the higher level of salivary thiocynate in smokers is responsible for the increased rate of endogenous nitrosation of proline in that group when compared with nonsmokers. Oxides of nitrogen in cigarette smoke do not appear to play a significant role.

Adult↗
PubMed1984

Organ specificity in the microsomal activation and toxicity of N-nitrosomethylbenzylamine in various species.

The microsomal metabolism of the rat esophageal carcinogen N-nitrosomethylbenzylamine (NMBZA) at the methylene carbon atom to yield benzaldehyde was studied in various organs of a number of species to determine the role of metabolic activation in the carcinogenicity or toxicity of the nitrosamine. In the Sprague-Dawley rat, NMBZA was metabolized by microsomes from liver, lung, and esophageal mucosa. In the F344 rat and rabbit, metabolic activity was present in both liver and esophageal mucosa, the only tissues studied in these species. In contrast, in the Syrian hamster and BALB/cByJ mouse, NMBZA debenzylation was undetectable in the esophagus but occurred at relatively high rates in liver, lung, and kidney. The forestomach mucosa exhibited undetectable levels of activity in the Sprague-Dawley rat and BALB/cByJ mouse, although in the hamster, it was present at a very low level. Administration of a dose of NMBZA acutely toxic to the rat (18 mg/kg i.p.) resulted in significant cellular damage only to the rat esophageal mucosa, no other tissues examined in the rat, hamster, or mouse being affected. These observations, together with the available data on carcinogenicity of the nitrosamine in the rat and rabbit, suggest that in the esophagus, at least, metabolic activation of NMBZA is necessary to elicit its toxic and/or carcinogenic effect. However, NMBZA is also metabolized at a high rate in the liver of all species but is not toxic or carcinogenic in this tissue, suggesting that other factors besides metabolic activation must be involved in the resistance of hepatocytes to the effects of the nitrosamine. Microsomes prepared from human esophageal mucosa from six patients metabolized NMBZA at rates that were either undetectable or approximately 70 times lower than in the Sprague-Dawley rat.

Animals↗
PubMed1984

Induction and suppression of N-nitrosomethylbenzylamine activation by microsomes from rat liver and esophagus.

Male Sprague-Dawley rats were pretreated with various chemicals to determine their effects on the microsomal activation of the esophageal carcinogen N-nitrosomethylbenzylamine [( NMBzA ) CAS: 937-40-6; N-methyl-N- nitrosobenzylamine ] in the rat esophagus and, for comparative purposes, in the rat liver. When rats were pretreated with NMBzA , little change in hepatic NMBzA - debenzylase activity was observed. In contrast, NMBzA metabolism in the esophagus was significantly (60-65%) reduced. Similarly, pretreatment of rats with disulfiram [CAS: 97-77-8; bis( diethylthiocarbamoyl )disulfide] caused a 40% decrease in esophageal metabolism, but it had no significant effect in the liver. Pretreatments with the methylenedioxybenzenes safrole [CAS: 94-59-7; 4-allyl-1,2-(methylenedioxy)benzene], isosafrole [CAS: 120-58-1; 1,2-(methylenedioxy)-4-propenylbenzene], and dihydrosafrole (CAS: 94-58-6; 1,2-(methylenedioxy)-4- propylbenzene ) caused a marked induction (twofold to fivefold) of the hepatic metabolism of NMBzA , but again esophageal metabolism was suppressed. The results indicate that esophageal metabolism of NMBzA is either unchanged or suppressed by the various chemical pretreatments, but hepatic metabolism of the nitrosamine is induced by the methylenedioxybenzenes .

Animals↗
PubMed1984

N-nitrosation of proline in smokers and nonsmokers.

Endogenous nitrosation of proline was investigated in smokers and nonsmokers. Volunteers consumed a volume of beet juice equivalent to 325 mg nitrate, and 1 hour later they consumed 500 mg proline. In separate experiments volunteers ingested proline alone. Twenty-four-hour urine samples were collected and analyzed for N-nitrosoproline. When proline alone was ingested, there was no significant difference in urinary nitrosoproline excretion between smokers and nonsmokers. When beet juice and proline were consumed, however, smokers produced approximately 2.5 times as much N-nitrosoproline as nonsmokers. Salivary thiocyanate levels were approximately 3.2 times higher in smokers compared to those in nonsmokers. Salivary nitrite levels of smokers and nonsmokers, either before or after beet juice consumption, were not different. Salivary nitrate concentrations, however, were higher in nonsmokers than in smokers after beet juice consumption but not before. Our results suggest that the higher level of salivary thiocyanate in smokers is responsible for the increased rate of endogenous nitrosation of proline in this group compared to the rate in nonsmokers. Nitrosating agents in cigarette smoke do not appear to play a significant role.

Adult↗
PubMed1983

Nitrate formation in rats exposed to nitrogen dioxide.

Sprague-Dawley rats exposed to atmospheres containing low levels of nitrogen dioxide (NO2) for 24 hr had increased levels of nitrate in their urine on the day of exposure and on the 3 subsequent days. The total increase in urinary nitrate was linearly related to the nitrogen dioxide concentration administered. We recovered in urine 8.4 +/- 1.1 mumol nitrate/ppm NO2/24-hr exposure (slope +/- 95% confidence limits) for 185-g rats. Both the linearity and magnitude of this effect imply that reaction with respiratory tract water is not a major pathway of NO2 absorption in the lung. Instead, our observations support the hypothesis that the major interaction of NO2 in the lung is with readily oxidizable tissue components to form nitrite. We estimate that 9.6 mumol of nitrite is formed in the respiratory tract of the rat per ppm NO2 per 24-hr exposure. We also estimate that humans breathing air containing 0.1 ppm NO2 have about 3.6 mg of nitrite formed in their respiratory tract per day.

Absorption↗
PubMed1983

Enzymatic reduction of beta-ketonitrosamines.

The reduction of N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-oxopropyl)propylamine (NOPPA) by hepatic and pancreatic cytosol and microsomes from Syrian golden hamsters and Sprague-Dawley rats has been examined. All hepatic fractions reduced both substrates, although the activity depended on the fraction tested and the cofactor employed (NADH or NADPH). Generally, hamster hepatic fractions contained higher activity than the rat hepatic fractions and BOP was a better substrate than NOPPA. Of the pancreatic fractions, only cytosol exhibited reductase activity. The hamster cytosol was able to utilise both cofactors, but the rat fraction exhibited activity only when NADPH was present. BOP was the better substrate for the pancreatic enzymes and in the presence of NADPH, the rat and hamster activities were about equal. These results suggest that the pancreatic reduction of BOP to HPOP is unlikely to be a significant factor in the species-specific induction of pancreatic cancer by BOP.

Animals↗
PubMed1982

Comparative tumor initiating activities of N-nitrosomethylbenzylamine and N-nitrosodimethylamine in rat liver.

The tumor initiating activities of nitrosomethylbenzylamine (NMBzA), an esophageal carcinogen, and nitrosodimethylamine (NDMA), a hepatocarcinogen, were compared in rat liver using modifications of the initiation assays of Tsuda et al. (Cancer Res., 40, 1157, 1980) and Pitot et al. (Nature, 271, 456, 1978). Equimolar doses of NMBzA or NDMA (33.5 mu-mol/kg) were injected i.p. into male Sprague-Dawley rats 18 h after partial hepatectomy. Following selection, foci of preneoplastic hepatocytes were detected by histochemical staining for gamma-glutamyltranspeptidase. Nitrosomethylamylamine (NMAmA), 115 mumol/kg), also an esophageal carcinogen, was tested in the assay of Tsuda et al., and nitrosodiethylamine (NDEA, 33.5 mumol/kg), a hepatic and esophageal carcinogen, was tested in the assay of Pitot et al. Both NDMA and NDEA induced significant increases in the number of preneoplastic foci above background. In contrast, neither NMBzA nor NMAmA increased the number of foci above background. Microsomes from regenerating liver had a lower capacity to metabolize both NDMA and NMBzA compared to microsomes from intact liver, but the decrease in activity was similar for both compounds. Neither NDMA nor NMBzA significantly inhibited the first wave of DNA synthesis in vivo in the regenerating liver. The results demonstrate that in contrast to NDMA and NDEA, NMBzA and NMAmA lack tumor initiating activity in the liver.

Animals↗
PubMed1982

Esophageal and hepatic microsomal metabolism of N-nitrosomethylbenzylamine and N-nitrosodimethylamine in the rat.

The metabolism of the rat esophageal carcinogen N-nitrosomethylbenzylamine (NMBzA) was studied using microsomes prepared from liver and esophageal mucosa of untreated male Sprague-Dawley rats. NMBzA was extensively metabolized to benzaldehyde, benzyl alcohol, and formaldehyde by hepatic microsomes. The rate of metabolism at the benzyl moiety was 10-fold higher than that at the methyl moiety. Mucosal microsomes metabolized NMBzA to benzaldehyde and formaldehyde at rates one-fifth and one-sixtieth of those in the liver, respectively; benzyl alcohol formation was undetectable. Esophageal metabolism of NMBzA was exclusively located in the mucosa, preferentially in the microsomal fraction, was reduced nicotinamide adenine dinucleotide phosphate dependent, and was inhibited by CO and 2-diethylaminoethyl-2,2-diphenylvalerate. A low level of cytochrome P-450 was detected in the mucosal microsomes. Whereas hepatic metabolism of NMBzA was inducible by phenobarbitone pretreatment, mucosal metabolism was not altered by either phenobarbitone or 3-methylcholanthrene pretreatment. The hepatocarcinogen N-nitrosodimethylamine was extensively metabolized by hepatic microsomes to formaldehyde, but demethylation was not detected in the microsomes from esophageal mucosa, a nontarget tissue. The results indicate that rat esophageal mucosa contains an enzyme system which metabolizes NMBzA at a high rate and exhibits properties typical of cytochrome P-450. This enzyme may play a role in determining which compounds induce tumors in rat esophagus.

Animals↗
PubMed1982

An analytical method for simple N-nitrosamides.

A clean-up method is described which sufficiently removes interfering chemicals from feces so that the colorimetric procedure of Preussmann & Schaper-Druckrey (1972), or HPLC with UV detection, can be used reliably to detect N-nitrosamides. The method has given reasonably good recoveries of four different N-nitrosamides intentionally added to feces. The method, or parts of it, should be applicable to the clean-up of other complex samples, such as food, biological tissues and body fluids.

Colorimetry↗
PubMed1982

Analysis and formation of nitrosamines in the human intestine.

The method employed for nitrosamine analysis gave high recovery values and did not produce artefactual nitrosamines. Nitrosation reactions are not catalysed by the microbial ecosystem of human feces. Rapid loss of nitrate and nitrite in feces also precludes nitrosamine formation, unless very high concentrations of precursors are present. These concentrations are not physiological and it is therefore unlikely that N-nitroso compounds form in the lower gastrointestinal tract of man.

Feces↗
PubMed1981

Quantitative determination of carcinogens and mutagens as alkylating agents following chemical activation.

Reaction of nitrosodiethylamine (NDEA) in a non-enzymatic, chemical activation system consisting of ascorbic acid, ferrous ions, EDTA and molecular oxygen yielded an alkylating intermediate that was detected by its reaction with 4-(p-nitrobenzyl)pyridine (PNBP) to yield a colored product. Reaction conditions for the chemical activation-detection system were optimized, allowing detection of approx. 10 mumol NDEA. The method detected a variety of acyclic and cyclic nitrosamines and other compounds that become alkylating agents only following oxidative metabolism.

Alkylating Agents↗
PubMed1981

Urinary metabolites of N-nitrosodipropylamine, N-nitroso-2-hydroxypropylpropylamine and N-nitroso-2-oxopropylpropylamine in the rat.

Analysis of 24 h urine samples of rats administered N-nitrosodipropylamine (NDPA), N-nitroso-2-hydroxypropylpropylamine (NHPPA) or N-nitroso-2-oxopropylpropylamine (NOPPA) showed that the major excretion product in each case was the beta-glucuronide of NHPPA. This conjugate was shown to be present at levels of about 5%, 80% and 50% of the administered dose for NDPA, NHPPA and NOPPA, respectively, based on exhaustive hydrolysis of the urine samples with beta-glucuronidase. Generally only low levels (less than 2%) of the unchanged nitrosamines or their unconjugated metabolites (NHPPA for administered NDPA and NHPPA for administered NOPPA) were detected. We were unable to detect N-nitrosomethylpropylamine or N-nitrosodimethylamine in the urine of any of the animals.

Animals↗
PubMed1981

Reactive intermediates from nitrosamines.

Metabolism of N-nitrosodi-n-propylamine by isolated rat liver fractions yielded both n-propanol and isopropanol, providing evidence for a reaction sequence, initiated by formation of the alpha-hydroxynitrosamine, that leads to formation of carbonium ions. Administration of N-nitrosodi-n-propylamine to rats led to formation of 7-n-propylguanine but not 7-isopropylguanine in hepatic DNA, showing that in the intact cell, the reaction sequence is intercepted by nucleophilic sites in DNA before a carbocation is formed. Alkylation of DNA therefore appears to occur primarily by a bimolecular reaction not involving free alkyl cations. N-nitrosodi-n-propylamine is also oxidized by rat liver microsomes by two consecutive beta-oxidation reactions to yield N-nitroso-2-oxopropylpropylamine. The latter agent leads to production of 7-methylguanine and O6-methylguanine in liver DNA following its administration to rats. The chemical nature of the ultimate methylating agent is unclear.

Animals↗