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Biomedical subjects

C B Chen

Publications and source records attributed to C B Chen.

44 records · Page 3Linked to original sources
PubMed1980

Metabolism in the F344 rat of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco-specific carcinogen.

The metabolism of the tobacco-specific carcinogen, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was studied in the F344 rat, in which it induces tumors of the nasal cavity, liver, and lung. When NNK was incubated with rat liver microsomes and a reduced nicotinamide adenine dinucleotide phosphate-generating system, metabolites resulting from alpha-hydroxylation, carbonyl reduction, and N-oxidation were isolated. alpha-Hydroxylation at the methylene carbon gave 4-oxo-4-(3-pyridyl)butanal, whereas alpha-hydroxylation at the methyl carbon gave myosmine and 4-hydroxyl-1-(3-pyridyl)butan-1-one. The formation of these products involved the intermediacy of electrophilic diazohydroxides or carbonium ions which may be proximate or ultimate carcinogens of NNK. Carbonyl reduction gave 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)butan-1-ol and N-oxidation yielded 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone. When rats were gavaged with NNK, the microsomal products of alpha-hydroxylation were not detected in the 48-hr urine. Compounds which presumably resulted from further oxidation or reduction of these products, 4-oxo-4-(3-pyridyl)butyric acid, 4-hydroxy-4-(3-pyridyl)butyric acid, and 4-hydroxy-1-(3-pyridyl)butan-1-ol, were isolated. 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)butan-1-ol and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl-N-oxide)-1 butanone were also urinary metabolites.

Animals↗
PubMed1978

Tobacco-specific nitrosamines: formation from nicotine in vitro and during tobacco curing and carcinogenicity in strain A mice.

The formation of tobacco-specific nitrosamines from the major tobacco alkaloid nicotine was examined. Detached leaf tobacco was fed either [2'-14C]nicotine or [2'-14C]nornicotine and air cured. The cured leaf was then analyzed for [2'-14C]N'-nitrosonornicotine ([2'-14C]NNN). The yield of [2'-14C]NNN was 0.007% from nornicotine and 0.009% from nicotine. Because the ratio of nicotine to nornicotine in conventional nicotine-type tobacco is 20-100:1, nicotine is considered to be the major precursor for the carcinogen NNN in tobacco. The formation of other nitrosamines from nicotine in vitro was then studied. Reaction of nicotine with NaNO2 gave rise to NNN, as well as to two other nitrosamines, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(N-methyl-N-nitrosamino)-4-(3-pyridyl)butanal (NNA). Analysis of market products revealed the presence of NNK (0.6-24 microgram/g) in chewing tobacco and snuff. The tumorigenic activity of NNN, NNK, and NNA in strain A mice was studied. NNK induced more lung adenomas per mouse than did NNN, whereas NNA was less active than NNN. In addition, two cases of undifferentiated carcinoma of the salivary glands occurred in the NNN experimental groups.

Adenoma↗
PubMed1978

Evidence for metabolic alpha hydroxylation of N-nitrosopyrrolidine.

Metabolic alpha hydroxylation of cyclic nitrosamines is important in the activation of these compounds to their ultimate carcinogenic forms. Direct evidence for this process is presented. Both alpha-hydroxynitrosopyrrolidine and 3-formyl-1-propanediazohydroxide, which are unstable intermediates resulting from alpha hydroxylation of nitrosopyrrolidine, were generated inaqueous solution from the stable precursors alpha-acetoxynitrosopyrrolidine and 4-(N-carbethoxy-N-nitrosamino)butanal. The major product resulting from the decomposition of slpha-hydroxynitrosopyrrolidine and 3-formyl-1-propanediazohydroxide was 2-hydroxytetrahydrofuran, the cyclic hemiacetal of 4-hydroxy-butyraldehyde. The same product was isolated as its dinitrophenylhydrazone derivative after incubation of rat liver microsomes with nitrosopyrrolidine and after treatment of rats with nitrosopyrrolidine.

Animals↗
PubMed1978

Chemical studies on tobacco smoke LVI. Tobacco specific nitrosamines: origins, carcinogenicity and metabolism.

Tobacco contains specific carcinogenic nitrosamines which are derived from nicotine. These compounds may be among the causative agents for the various cancers (lung, oral cavity, oesophagus, bladder and pancreas) which are associated with tobacco usage. The major tobacco specific nitrosamine is N'-nitrosonornicotine (NNN), which has been detected in both unburned tobacco (0.3-90.6 ppm) and cigarette mainstream smoke (137-238 ng/cig.). Studies with labelled precursors showed that the major source of NNN formed during curing of tobacco was nicotine, rather than nornicotine. The transfer rate of NNN from tobacco to mainstream smoke was 11.3%; about half the NNN present in smoke therefore originated from tobacco, with the remainder being formed during smoking. Model studies of the reaction of nicotine and nitrite showed that, in addition to NNN, two other nitrosamines, 4-(N-methyl-N-nitrosamino)-4-(3-pyridyl)-1-butanal (NNA) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were formed. Analysis of tobacco revealed the presence of NNK in chewing tobacco and snuff (0.6-2.4 ppm). A comparative bioassay of NNN, NNK and NNA in strain A mice indicated that NNK was more tumorigenic than NNN and that NNA was inactive. NNN, which had previously been shown to induce oesophageal and nasal cavity tumours in rats, also was a moderately active carcinogen in the Syrian golden hamster, giving tracheal tumours. A study of the metabolism of cyclic nitrosamines was initiated. Metabolic alpha-hydroxylation of nitrosopyrrolidine, which is thought to be the critical step in activation of this compound, was demonstrated by detection in vitro and in vivo of 2-hydroxytetrahydrofuran, which was the product of decomposition of alpha-hydroxynitrosopyrrolidine. The metabolism of the related cyclic nitrosamine, NNN, is currently under investigation, with emphasis on metabolites resulting from alpha- and beta-hydroxylation. These analytical and metabolic studies are intended to clarify the possible relationship of tobacco-specific nitrosamines and site-specific cancers in tobacco users.

Anabasine↗
PubMed1978

High pressure liquid chromatographic assay for alpha hydroxylation of N-nitrosopyrrolidine by isolated rat liver microsomes.

A high-pressure liquid chromatographic assay for alpha hydroxylation of N-nitrosopyrrolidine by isolated hepatic microsomes was developed. Mixtures consisting of N-nitrosopyrrolidine, microsomes, and an NADPH-generating system were incubated at 37 degrees. The major product of alpha hydroxylation of N-nitrosopyrrolidine, 2-hydroxytetrahydrofuran, was trapped by the addition of 2,4-dinitrophenylhydrazine reagent to form 4-hydroxybutyraldehyde-2,4-dinitrophenylhydrazone. The latter was quantified by reverse-phase high-pressure liquid chromatography. Under optimal conditions, as determined by varying protein and substrate concentrations, the alpha hydroxylation of N-nitrosopyrrolidine was linear for at least 90 min and showed characteristics typical of the microsomal mixed-function oxidase system, such as inhibition by CO and induction by pretreatment of male F-344 rats with Aroclor. N-Nitrosopyrrolidine exhibited type II spectral changes upon interaction with isolated hepatic microsomes. A close correspondence between binding affinity and alpha hydroxylation of N-nitrosopyrrolidine was observed.

Animals↗