Michael C. Archer

Environmental nitroso compounds: reaction of nitrite with creatine and creatinine.

Creatine reacts with nitrite under acid conditions to produce first sarcosine and then N-nitrososarcosine, which is a weak carcinogen in the rat. Creatinine reacts with acidified nitrite to produce either creatinine-5-oxime or 1-methylhydantoin-5-oxime, depending on reaction conditions. The toxicity and environmental significance of these compounds is not yet known.

Nitrosamine carcinogenicity: A quantitative Hansch-Taft structure-activity relationship

Statistically significant correlations have been demonstrated between carcinogenic activity, water-hexane partition coefficients and electronic factors for an extensive series of N-nitroso compounds. Electronic factors were expressed by the Taft sigma* values of substituents on the carbon atoms alpha to the N-nitroso group. Such correlations indicate that transport of the carcinogen to its active site has an important effect on its potency. The correlations also implicate reactivity at the alpha-carbon in the determination of carcinogenic activity and point out various structural types which do not follow the general rule.

Mechanism of alkylation by N-nitroso compounds: Detection of rearranged alcohol in the microsomal metabolism of N-nitrosodi-n-propylamine and base-catalyzed decomposition of N-n-propyl-N-nitrosourea

Metabolism of N-nitrosodi-n-propylamine by an isolated rat liver microsomal fraction yielded 17% isopropanol and 83% n-propanol (expressed as a percentage of total propanol formed). Base-catalyzed decomposition of N-n-propyl-N-nitrosourea yielded 39% isopropanol and 61% n-propanol. The values provide evidence for involvement of carbocations in both of these reactions.

Alkylation of nucleic acids by N-nitrosodi-n-propylamine: Evidence that carbonium ions are not significantly involved

Administration of N-nitrosodi-n-propylamine to rats leads to the formation of 7-n-propylguanine but not 7-isopropylguanine in hepatic DNA. For RNA, a small amount of the rearranged adduct is formed. Alkylation of DNA and RNA therefore appears to occur primarily via a bimolecular reaction rather than a unimolecular pathway involving free alkyl cations.

Microsomal metabolism of N-nitrosodi-n-propylamine: formation of products resulting from α-and β-oxidation

We have identified propionaldehyde, n-propranolo, isopropanol and N-nitroso-2-hydroxy-propylpropylamine following incubation of N-nitrosodi-n-propylamine with a microsomal fraction from rat liver. Based on the yields of the various products, we have shown that beta-oxidation occurs at about 15% of the level of alpha-oxidation, beta- as well as alpha-oxidation was shown to be carried out by the microsomal mixed function oxidase system. N-nitroso-2-hydroxy-propylpropylamine is further oxidized by the microsomal preparation to yield N-nitroso-2-oxopropylpropylamine.

Reactions of nitrosamines in the Udenfriend system: Principal products and biological activity ☆

Abstract Reaction of diethylnitrosamine in the non-enzymatic, ascorbic acid-dependent hydroxylating system of Udenfriend yielded N -nitroso-2-(ethylamino)-ethanol as the major product extracted into methylene chloride. The major product derived from nitrosopiperidine in the same system was N -nitroso-4-piperidone. These products, however, were mutagenic to Salmonella typhimurium TA 1535 only when activated by a rat liver microsomal preparation.

Dietary effects of the pharmacokinetics of three carcinogenic nitrosamines

Abstract The concentrations of N -nitrosodimethylamine (DMN), N -nitrosodiethylamine (DEN), and N -nitrosodibutylamine (DBN) were monitored as a function of time in the blood and liver of rats fed either a normal diet or a diet marginally deficient in lipotropes. The disappearance of each nitrosamine from the blood showed first-order kinetics. Hepatic clearance of DEN and DBN also followed first-order kinetics, but the time dependence of DMN concentration in liver tissue showed an anomalous behavior. Diet-related differences in the pharmacokinetic data did not explain the variations in carcinogenicity caused by diet.

Chromatographic separation of conformers of substituted asymmetric nitrosamines.

The syn and anti conformers of N-nitrosoproline, N-nitrososarcosine and N-nitroso-2-(ethylamino)-ethanol, have been separated by liquid chromatography. These conformers result from hindered rotation about the N-N bond. Separation was achieved using adsorption, reversed-phase, and ion-exchange modes. For the nitroso-amino acids, a shift in the equilibrium conformer concentration was observed with changes in pH.

Methylation of DNA by N-nitroso-2-oxopropylpropylamine: formation of O6- and 7-methylguanine and studies on the methylation mechanism.

Abstract Administration of N -nitroso-2-oxopropylpropylamine (NOPPA) to rats formed both 7-methylguanine and O 6 -methylguanine in liver DNA. The O 6 - to 7-methylguanine ratio (0.07 after 12 hr) was similar to the ratio of the methylated guanines obtained with N -nitrosodimethylamine (NDMA) for the same time period. NOPPA hydrolyzed to yield N -nitrosomethylpropylamine (NMPA), but only in solutions at high pH. We found no evidence for an enzyme in rat liver capable of converting NOPPA to NMPA.

[58] Separation of folic acid derivatives and pterins by high-performance liquid chromatography

Publisher Summary This chapter discusses the separation of folic acid derivatives and pterins, by high-performance liquid chromatography. For this study, folic acid, 7,8-dihydrofolic acid, 5,6,7,8-tetrahydrofolic acid, 5-methyltetrahydrofolic acid, and p-aminobenzoylglutamic acid were purchased from Sigma Chemical Co. 5,10-Methenyltetrahydrofolic acid and 10-formyltetrahydrofolic acid were prepared by the method of Rabinowitz. The 5,10-methylenetetrahydrofolic acid was prepared by the method of Huennekens et al. N(10)‑nitrosofolic acid was prepared by the method of Cosulich and Smith. 2‑Hydroxy-N(10)-nitrosofolic acid and 2-hydroxyfolic acid were prepared by the method of Angier et al. Xanthopterin, pterin, and pterin-6-carboxylic acid were purchased from Sigma. Pterin-6-carboxaldehyde was prepared by the method of Waller et al. Because most reduced derivatives of folic acid are extremely labile to oxidation, by air, 2-mercaptoethanol is normally added to the solutions, containing 7,8-dihydro and 5,6,7,8-tetrahydro derivatives. 2-Mercaptoethanol absorbs at 254 nm and interferes with the detection of chromatographic peaks. This chapter discusses the separation of the three oxidation states of folic acid. Separation of N(5)-and N(10)-substituted tetrahydrofolates is described in the chapter. Separation of the products of nitrosation of folic acid is also elaborated in the chapter in detail.