Search PubMed⌕ Search

Biomedical subjects

S S Hecht

Publications and source records attributed to S S Hecht.

At least 325 records · Page 18Linked to original sources
PubMed1979

Synthesis and mutagenicity of 5,11-dimethylchrysene and some methyl-oxidized derivatives of 5-methylchrysene.

A series of compounds structurally related to the carcinogen and mutagen 5-methylchrysene (1) was synthesized and tested for mutagenicity toward S. typhimurium TA 100. The compounds prepared were 5,11-dimethylchrysene (2), 5-(hydroxymethyl)chrysene (3), 5-(acetoxymethyl)chrysene (4), 5-carbomethoxychrysene (5), 5-(hydroxymethyl)-1,2,3,4-tetrahydrochrysene (6), 5-carbomethoxy-1,2,3,4-tetrahydrochrysene (7), and 5H-chryseno[4,5-bcd]pyran-5-one (31). When tested in the presence of rat liver homogenate, 1 and 2 were active while 3--7 were less mutagenic than 1; 31 was highly mutagenic. The mutagenicity of 1 and 2 contrasts with the low activity of 5,12-dimethylchrysene, which supports the generalization that the structural requirements favoring activity are a bay-region methyl group and a free peri position, both adjacent to an unsubstituted angular ring. The low activity of 3--7 indicates that methyl oxidation is not an important activation process for 1. This agrees with previous studies in which the major proximate mutagen and carcinogen of 1 was identified as 1,2-dihydro-1,2-dihydroxy-5-methylchrysene.

Animals↗
PubMed1979

Assay for microsomal alpha-hydroxylation of N'-nitrosonornicotine and determination of the deuterium isotope effect for alpha-hydroxylation.

A high-pressure liquid chromatographic assay was developed for microsomal alpha-hydroxylation (2'-hydroxylation and 5'-hydroxylation) of N'-nitrosonornicotine. N'-Nitrosonornicotine was incubated with rat liver microsomes and a reduced nicotinamide adenine dinucleotide phosphate-generating system at 37 degrees. After addition of 2,4-dinitrophenylhydrazine reagent, the mixtures were analyzed by reverse-phase high-pressure liquid chromatography. The 2,4-dinitrophenylhydrazones of 4-hydroxyl-1-(3-pyridyl)-1-butanone and 4-hydroxy-1-(3-pyridyl)-butanal, which are the products of 2'-hydroxylation and 5'-hydroxylation, were quantified by ultraviolet light detection at 254 nm. Km's for 2'-hydroxylation and 5'-hydroxylation of N'-nitrosonornicotine by liver microsomes from Aroclor-treated male F-344 rats were 1.81 and 1.96 mM, while Vmax's were 0.53 and 1.05 nmol/min/mg protein, respectively. Aroclor pretreatment of rats resulted in a 20-fold induction of 2'-hydroxylation, but only a 1.9-fold induction of 5'-hydroxylation. The deuterium isotope effect for alpha-hydroxylation of N'-nitrosonornicotine was determined by comparing the rates of 2'-hydroxylation and 5'-hydroxylation of N'-nitrosonornicotine, N'-[2',5',5'-D]nitrosonornicotine, N'-[2'-D]nitrosonornicotine, and N'-[5',5'-D]nitrosonornicotine. The deuterium isotope effect (Vmax H/Vmax D) was 2.4 to 2.7 for 5'-hydroxylation and 1.2 for 2'-hydroxylation.

Animals↗
PubMed1979

Enhanced metabolism and mutagenesis of nitrosopyrrolidine in liver fractions isolated from chronic ethanol-consuming hamsters.

The effect of chronic ethanol consumption on the ability of isolated liver fractions to metabolize the carcinogen N-nitrosopyrrolidine (NPY) was examined. Microsomal fractions of treated animals exhibited increased rates of alpha-hydroxylation of NPY. Similar increases in the specific activities of aniline hydroxylase, reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase, and the specific content of cytochrome P-450 were also observed. In contrast, no differences in the specific activities of benzo(a)pyrene hydroxylase or glucose-6-phosphatase were observed. Liver postmitochondrial supernatants from ethanol-consuming animals were able to produce 5 times more mutants than did control preparations. It is concluded that alpha-hydroxylation of NPY is probably the mechanism by which NPY is converted to a mutagen and that this pathway can be induced by ethanol.

Alcoholism↗
PubMed1978

Comparative tumor initiating activity of 10-methylbenzo-[a]pyrene, 7,10-dimethylbenzo[a]pyrene and benzo[a]pyrene.

The tumor initiating activity on mouse skin of benzo[a]pyrene (BaP), 7,10-dimethylBaP, and 10-methylBaP was determined. Each compound was tested at initiating doses of 50 microgram and 100 microgram with promotion by application 3 times weekly of 2.5 microgram tetradecanoylphorbol acetate. BaP induced tumors in 40% (100 microgram) and 25% (50 microgram) of the animals. No tumors were observed in either group treated with 7,10-dimethylBaP. In the groups treated with 10-methyl-Bap, the incidence of tumor bearing animals was 20% at both doses. These results and the results of previous studies on other methylated BaP derivatives suggest that the mechanism of activation of these compounds is similar to that observed for the parent hydrocarbon and probably involves formation of an angular ring diol-epoxide or epoxide.

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

1,2-dihydro-1,2-dihydroxy-5-methylchrysene, a major activated metabolite of the environmental carcinogen 5-methylchrysene.

The metabolic activation of the environmental carcinogen 5-methylchrysene was studied by combining high-pressure liquid chromatographic analysis of metabolites formed in vitro with assays of these metabolites for mutagenic activity toward Salmonella typhimurium. Metabolites were formed by incubation of 5-methylchrysene with the 9000 x g supernatant from Aroclor-treated rat livers. With the use of reverse-phase columns, the metabolites were resolved into nine peaks, A to I. Each peak was collected and tested for mutagenicity with activiation. Significant mutagenic activity was observed primarily in peak E and to a lesser extent in peak D. None of the other metabolites showed significant mutagenic activity. The major mutagenic metabolite (peak E) was identified as 1,2-dihydro-1,2-dihydroxy-5-methylchrysene (7.0% from 5-methylchrysene); Peak D was 7,8-dihydro-7,8-dihydroxy-5-methylchrysene (2.6% from 5-methylchrysene). Other metabolites included 9,10-dihydro-9,10-dihydroxy-5-methylchrysene, 9-hydroxy-5-methylchrysene, 7-hydroxy-5-methylchrysene, 1-hydroxy-5-methylchrysene, and 5-hydroxymethylchrysene. These results indicate that 1,2-dihydro-1,2-dihydroxy-5-methylchrysene is a major proximate mutagen of 5-methylchrysene.

Animals↗
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↗
PubMed1977

A study of tobacco carcinogenesis. XV. Effects of N'-nitrosonornicotine and N'-nitrosoanabasine in Syrian golden hamsters.

N'-Nitrosonornicotine (NNN) and N'-nitrosoanabasine (NAB) were synthesized and injected subcutaneously three times weekly in male and female Syrian golden hamsters for 25 weeks (total dose 375 mg). N-Nitrosopiperidine (NPD) served as positive control (total dose 150 mg). Within 83 weeks 12 out of 19 hamsters given NNN had developed tracheal tumors, 1 had a carcinoma of the nasal cavity. During the same time none of the hamsters given NAB developed tumors, whereas all 20 hamsters given NPD developed tracheal tumors and about 50% had additional neoplasms in the nasal cavity. Under the described conditions and in comparison to NPD, NNN appears to be a moderately active tumorigenic agent in the upper respiratory tract of Syrian hamsters, whereas NAB is inactive.

Anabasine↗
PubMed1977

Origin in tobacco smoke of N'-nitrosonornicotine, a tobacco-specific carcinogen.

To evaluate risk factors and to approach methods of reduction of the carcinogenic potential of cigarette smoke, the transfer rate of N-nitrosonornicotine in a popular U.S. blended cigarette into mainstream smoke was quantitatively determined. The mean transfer rate was 11.3%; thus approximately 46% of the tobacco-specific carcinogen in the smoke came from the tobacco, and the remainder was synthesized during smoking.

Nicotine↗