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At least 19 recordsLinked to original sources
PubMed1998

Carcinogenicity of 1-hydroxy-3-methylcholanthrene and its electrophilic sulfate ester 1-sulfooxy-3-methylcholanthrene in Sprague-Dawley rats.

Previous experiments have demonstrated that the carcinogen 1-hydroxy-3-methylcholanthrene is a metabolite of 3-methylcholanthrene. 1-Sulfooxy-3-methylcholanthrene, prepared by chemical synthesis from 1-hydroxy-3-methylcholanthrene, was shown to be a direct acting electrophilic mutagen and DNA damaging agent. These results imply that 1-hydroxy-3-methylcholanthrene could be metabolically activated to an ultimate electrophilic and carcinogenic form of 1-hydroxy-3-methylcholanthrene and 3-methylcholanthrene in a reaction catalyzed by 3'-phosphoadenosine-5'-phosphosulfate-dependent sulfotransferase activity. 1-Hydroxy-3-methylcholanthrene and its aralkylating reactive ester, 1-sulfooxy-3-methylcholanthrene, were individually administered to groups of 12 female Sprague-Dawley rats at a 0.2 mumol dose, three times weekly, for 20 doses. 1-Sulfooxy-3-methylcholanthrene induced sarcomas at the site of injection in 8 of 12 rats (66%) by 52 weeks, whereas 1-hydroxy-3-methylcholanthrene induced sarcomas at the site of injection in 5 of 12 rats (42%) by 52 weeks. These results, taken together with the results of previous experiments, strongly support the hypothesis that the activated electrophilic mutagen 1-sulfooxy-3-methylcholanthrene plays a major role as an ultimate electrophilic and carcinogenic form of 1-hydroxy-3-methylcholanthrene, a major metabolite of 3-methylcholanthrene.

Animals↗
PubMed1955

Are carcinogens responsible for the superimposed neoplastic changes occurring in mouse tumor cells? The effect of methylcholanthrene and urethane on pulmonary adenomas and of methylcholanthrene on mammary carcinomas.

Three spontaneous pulmonary adenomas of C mice, morphologically resembling those induced by methylcholanthrene or urethane, were propagated in host after host under conditions such that the neoplastic cells were directly exposed, while proliferating, to one or the other of these agents. The successive periods of test lasted for more than a year in some instances, the total exposure to the carcinogens far exceeding that required to change normal pulmonary cells into adenoma cells. One of the adenomas remained unaltered, and the others underwent cancerous changes; but these took place with equal frequency in the control growths, and their occurrence was neither hastened nor delayed by the carcinogens. Two polymorphous mammary carcinomas of "milk-factor" type, with the characteristic tendency to form acini and tubules, were exposed to methylcholanthrene in the same way as the pulmonary adenomas and for periods quite as long. Their cells continued to differentiate, and in other respects underwent no significant change. Urethane had no influence on the rate of growth of the adenomas exposed to it; methylcholanthrene, on the other hand, markedly retarded the enlargement both of them and of the mammary tumors. Its inhibitory influence was not passed on from cell to cell however; when freed of the carcinogen by further transplantation, the retarded tumors grew as fast as the controls. Furthermore the retardation caused no evident delay in the occurrence of cancerous changes in the adenomas. One of the adenomas was maintained in twelve parallel lines while under test and new tumors arose in nine of them, the earliest appearing more than fifteen months after initial transfer of the growth. Always it was an adenoma solidum, this appearing almost concurrently in eight of the nine lines. In six of them it was soon followed by carcinomas, the sequence of events and the morphological findings both indicating that they had derived from it. Individually the cancers were widely various, but they were similar on the whole from line to line. Carcinomas of a wholly different aspect arose from the other adenoma undergoing cancerous change, and they were not preceded by adenoma solidum. In both instances the character of the superimposed neoplastic alterations seemed to have been determined by some inherent trait of the adenoma concerned.

Adenoma↗
PubMed1990

9,10-Dihydroxy-9,10-dihydro-3-methylcholanthrene-2-one: a principal metabolite of the potent carcinogen 3-methylcholanthrene-2-one by rat liver microsomes.

A principal metabolite, formed in the metabolism of the potent carcinogen 3-methylcholanthrene-2-one (3MC-2-one) by liver microsomes from either untreated, or phenobarbital-treated or 3-methylcholanthrene (3MC)-treated rats, was isolated by reversed-phase HPLC. This metabolite has been identified as a 9,10-dihydrodiol with a (9R,10R):(9S,10S) enantiomer ratio of approximately 84:16 by all three rat liver microsomal preparations. The 9,10-dihydrodiol metabolite and its NaBH4 reduction products [a pair of diastereomeric 9,10-dihydroxy-9, 10-dihydro-2-OH-3MC (2-OH-3MC 9,10-dihydrodiols)] were characterized by UV-visible absorption, mass, and circular dichroic spectral, and chiral stationary phase HPLC analyses. Identification of 9,10-dihydroxy-9,10-dihydro-3MC-2-one (3MC-2-one 9,10-dihydrodiol) as the predominant metabolite of the potent carcinogen 3MC-2-one suggests that 3MC-2-one may be metabolically activated to a bay region 9,10-diol-7,8-epoxide, similar to the previously established metabolic activation pathways of 3MC and 1-hydroxy-3-methylcholanthrene (1-OH-3MC).

Animals↗
PubMed1995

Intrinsic mutagenicity and electrophilicity of 1-sulfooxy-3-methylcholanthrene: implications for metabolic activation of the carcinogen 3-methylcholanthrene.

Hydroxylation of a meso-anthracenic carbon atom with subsequent formation of a reactive ester bearing a good leaving group (e.g., sulfate) has been proposed as a possible biochemical mechanism responsible for DNA binding, mutagenicity and tumorigenicity of 3-methylcholanthrene, one of the most potent carcinogenic polycyclic aromatic hydrocarbons in experimental animals. In support of this supposition, the chemically synthesized sulfuric acid ester, 1-sulfooxy-3-methylcholanthrene (1-SMC) was directly mutagenic in bacteria and covalently bound to DNA without metabolic activation. The intrinsic mutagenicity of this reactive ester was significantly potentiated by addition of extra acetate or chloride anions to the media. Reduced glutathione and ascorbic acid protected against 1-SMC-induced mutagenesis. These findings suggest 1-SMC as a potential ultimate electrophilic and tumorigenic metabolite of 3-methylcholanthrene.

Biotransformation↗
PubMed1990

Effect of different doses of 3-methylcholanthrene on the localization of the 3-methylcholanthrene-inducible isoenzymes of cytochrome P450 within the centrilobular and periportal zones of the rat liver.

Immunohistochemical staining techniques were used to investigate the localization of the 3-methylcholanthrene inducible isoenzymes (P450 IA1 and IA2) in the rat liver. The rats were induced with different doses of 3-methylcholanthrene, ranging from 2.5 to 25 mg/kg body weight. A heterogeneous induction pattern was observed with induction doses of 2.5; 5; 7.5 and 10 mg/kg body weight with the highest concentration of the isoenzymes around the central vein. With a dose of 25 mg/kg body weight, a homogeneous pattern was found. Induction with a dose of 15 mg/kg body weight resulted in an intermediate situation.

Animals↗
PubMed1986

Effect of 3-methylcholanthrene on atherosclerosis in two congenic strains of mice with different susceptibilities to methylcholanthrene-induced tumors.

Inbred mouse strains AKXL-38 and AKXL-38a are congenic strains that differ at the Ah locus, a gene which affects the inducibility of the cytochrome P-450 enzymes. The Ah-responsive strain, AKXL-38a, is more susceptible to 3-methylcholanthrene-induced tumors than the Ah-nonresponsive strain, AKXL-38. We previously reported that 3-methylcholanthrene (MC) increased the number and the size of atherosclerotic lesions in a dose-dependent fashion. We now demonstrate that the effect of MC is greater in Ah-responsive mice than in Ah-nonresponsive mice indicating that Ah-responsive mice not only are more susceptible to MC-induced cancer but also are more susceptible to MC-enhanced atherosclerosis. Mice that received atherogenic diet for 14 weeks but no MC had 1.3-1.4 lesions/mouse regardless of genetic type. When mice were treated with MC, the number of lesions increased to 2.1 +/- 0.1 (SE) in Ah-nonresponsive mice, 2.6 +/- 0.2 in Ah-responsive mice, and 2.3 +/- 0.2 in the F1 hybrid. The total area involved in lesions was 9.3-12.6 micron2 in untreated animals. When mice were treated with MC, the total lesion area increased to 23.5 +/- 5.2 micron2 in Ah-nonresponsive mice, to 43.9 +/- 6.6 micron2 in Ah-responsive mice, and to 36.2 +/- 4.8 micron2 in F1 hybrids. Thus MC increased the lesion area in both strains of mice, but the increase was significantly greater in Ah-responsive than in Ah-nonresponsive animals. High density lipoprotein levels were not significantly affected by MC treatment or Ah genotype. In order to determine whether the increased susceptibility to MC-induced atherosclerosis segregated with the Ah gene, AKXL-38 and AKXL-38a mice were mated and the F1 progeny were backcrossed to the Ah-nonresponsive parent. Backcross progeny were tested for Ah genotype by zoxazolamine sleeping time. Measurements of lesions showed that increased susceptibility to MC-enhanced atherosclerosis segregated with the Ah locus.

Animals↗
PubMed1981

[Effects of 3-methylcholanthrene and 3-methylcholanthrene plus piracetam on the gamma-amino-butyric acid (GABA) content of several cerebral regions (author's transl)].

Chronic application of Piracetam decreases 3-methylcholanthrene-induced increased GABA content in the brains of rats and delays tumor appearance. The most active inhibitor of GABA-transaminase, amino oxyacetic acid (AOAA), increases the GABA content in the brain and appears to increase the tumor rate in 3-MC rats. Despite some reservations in view of results derived from investigations of only two compounds (3-MC and Piracetam) we suppose that a relation exists between effects on central nervous system and peripheral carcinogenesis. We will try to support our hypothesis further by using other compounds influencing the GABA-content of the brain.

Aminooxyacetic Acid↗
PubMed1978

The identification of 3-methylcholanthrene-9,10-dihydrodiol as an intermediate in the binding of 3-methylcholanthrene to DNA in cells in culture.

Two metabolites of 3-methylcholanthrene (3MC), previously shown to be precursors of the DNA-bound form of 3MC observed in embryo cells in culture, were prepared from 3MC by microsomal metabolism and isolated by high pressure liquid chromatography (HPLC). From HPLC analysis of the metabolites of 3MC, from mass spectrometric analysis and from comparison with the fluorescence spectra of all 5 possible dihydrodiols of the alkylated benzanthracenes, it was deduced that one of the precursor metabolites was a 9,10-dihydrodiol of 3MC while the other was a 1 or 2-hydroxy derivative thereof.

Animals↗
PubMed1982

Fungal oxidation of 3-methylcholanthrene: formation of proximate carcinogenic metabolites of 3-methylcholanthrene.

The filamentous fungus, Cunninghamella elegans, was found to metabolize the potent carcinogen, 3-methylcholanthrene (3-MC) to 1-hydroxy-3-MC, 2-hydroxy-3-MC, 1-keto-3-MC, 2-keto-3-MC and trans-9,10-dihydrodiols of 1-hydroxy-3-MC. In addition several unidentified derivatives of 3-MC were found. The metabolites formed were separated by high pressure liquid chromatography (HPLC) and identified by comparison of retention times, absorbance, fluorescence and mass spectra with those of synthetic standards. Incubation of (+/-)-1-hydroxy-3-MC and (+/-)-2-hydroxy-3-MC with cells of C. elegans indicated that 1-hydroxy-3-MC is metabolized to form diasteromerically related trans-9,10-dihydrodiols of 1-hydroxy-3-MC. Experiments with 3-[14C]MC showed that over a 48-h period, 8.7% of the hydrocarbon was oxidized to organic solvent-soluble metabolic products. Most of the metabolites were polar products, some of which co-chromatographed with trans-9,10-dihydrodiols of 1-hydroxy-3-MC. The results show that C. elegans has the ability to oxidize 3-MC to metabolites that have been implicated as proximate carcinogenic forms of 3-MC in higher organisms.

Biotransformation↗
PubMed1990

1-Hydroxy- and 2-hydroxy-3-methylcholanthrene: regioselective and stereoselective formations in the metabolism of 3-methylcholanthrene and enantioselective disposition in rat liver microsomes.

Absolute configurations of enantiomeric 1-hydroxy-3-methylcholanthrene (1-OH-3MC) and 2-hydroxy-3-methyl-cholanthrene (2-OH-3MC) were determined by the exciton chirality circular dichroism (CD) method as their p-nitrobenzoate derivatives. Enantiomers of 1-OH-3MC were resolved by HPLC using a column packed with chiral stationary phase (CSP) (R)-N-(3,5-dinitrobenzoyl)phenylglycine covalently bonded to gamma-aminopropylsilanized silica. Enantiomers of 2-OH-3MC were resolved as diastereomeric (-)-methoxyacetates by normal-phase HPLC. 1-OH-3MC and 2-OH-3MC, formed in the metabolism of 3MC by liver microsomes from untreated, phenobarbital (PB)-treated and 3MC-treated male Sprague-Dawley rats, were first isolated as a mixture by reversed-phase HPLC and subsequently separated by normal-phase HPLC. Concentration ratios of [1-OH-3MC]:[2-OH-3MC] formed in the metabolism of 3MC by three rat liver microsomal preparations (at 0.5 mg protein per ml of incubation mixture and an incubation time of 10 min) were found to be: 30:70 (control), 21:79 (PB treated) and 10:90 (3MC treated) respectively. R/S enantiomer ratios of 1-OH-3MC formed in the metabolism of 3MC by three rat liver microsomal preparations were determined by CSP HPLC: 35:65 (control), 39:61 (PB treated) and 46:54 (3MC treated) respectively. R/S enantiomer ratios of 2-OH-3MC formed in the metabolism of 3MC by three rat liver microsomal preparations were determined by CD spectral data: 14:86 (control), 6:94 (PB treated) and 6:94 (3MC treated) respectively. Metabolism of racemic 1-OH-3MC and 2-OH-3MC by all three rat liver microsomal preparations was found to be substrate enantioselective; the rate of 1S-OH-3MC metabolism was faster than that of 1R-OH-3MC, whereas the rate of 2R-OH-3MC metabolism was faster than that of 2S-OH-3MC.

Animals↗
PubMed1986

The reaction of a 3-methylcholanthrene diol epoxide with DNA in relation to the binding of 3-methylcholanthrene to the DNA of mammalian cells.

DNA prelabelled in the purine or pyrimidine bases was reacted with anti-7,8-epoxy-trans-9,10-dihydroxy-7,8,9,10-tetra-hydro-3-methylchol ant hrene (anti-3MCDE). Enzymic degradation and column chromatography allowed the isolation of a number of hydrocarbon--nucleoside derivatives. The major product was shown to result from reaction with the 2-amino-group of guanine, but minor products containing guanine, adenine and cytosine were also obtained. One of the minor products, probably resulting from reaction at N7-guanine, led to rapid depurination. Anti-3MCDE was an efficient mutagen at the hprt-locus of V79 cells even at low doses which caused no cytotoxicity. In all the above properties anti-3MCDE closely resembled the anti-diol-epoxide of benzo[a]-pyrene. A similar study of DNA derived from mouse embryo cells which had been exposed to tritium labelled 3-methylcholanthrene (3MC) yielded a series of nucleoside adducts, only a minority of which were derived by reaction of anti-3MCDE with DNA. Two major in vivo products were shown to derive from 3MC alcohols, particularly 3-hydroxymethyl-cholanthrene, and probably involved both syn and anti-diol-epoxide metabolites.

Adenine↗
PubMed1991

Long-term (imprinting) effects of transplacental treatment of mice with 3-methylcholanthrene or beta-naphthoflavone on hepatic metabolism of 3-methylcholanthrene.

Foetal mice of genotype AhbAhd (responsive to induction of metabolism of polycyclic aromatic hydrocarbons [PAH]) or AhdAhd (non-responsive) were exposed transplacentally on gestation day 17 to a single dose of 3-methylcholanthrene (MC, 5-175 mg/kg) with or without prior treatment on day 15 with beta-naphthoflavone (beta NF, 150 mg/kg). The mothers were themselves either induction-responsive [(C57BL/6 x DBA/2)F1] or non-responsive (DBA/2). Metabolism of [14C]MC by homogenates of livers from the transplacentally-exposed offspring was quantified at 9 months of age (first experiment) or 13 months (second experiment) with or without prior inducing treatment with MC. The foetal exposure to MC had a permanent effect on MC metabolism by the adult hepatic homogenates in both experiments. In most instances the effect was positive in direction and small in magnitude (15-30%). It was dose-dependent with regard to transplacental MC, occurred in both induced (AhbAhd) and non-induced (AhdAhd) individuals, and was significant only when the mother and/or the foetus was inducible. beta NF itself did not have a positive imprinting effect. In some cases it either reduced or potentiated the long-term imprinting effect of MC, depending on the MC dose and the phenotype of the mother. These results confirm that transplacental exposure to a carcinogenic PAH may permanently alter metabolism of the chemical in later life, and indicate that this imprinting action is dependent on induced metabolism of the chemical in the mother and/or foetus.

Animals↗
PubMed1985

Protection against tumorigenesis by 3-methylcholanthrene in mice by beta-naphthoflavone as a function of inducibility of methylcholanthrene metabolism.

The noncarcinogenic enzyme inducer beta-naphthoflavone (beta-NF) causes an increase in both rate of activation and of detoxification of polycyclic aromatic hydrocarbon carcinogens in tissues of mice of induction-responsive strains. An experiment was carried out to test whether pretreatment with beta-NF would potentiate, protect against, or have no effect on the tumorigenicity of methylcholanthrene (MC) administered intragastrically to mice of varying responsiveness to induction of MC metabolism. The mouse strains used were C57BL/6, BALB/c, and C3H (inbred, highly responsive to induction), Swiss (random-bred, moderately responsive), and DBA/2 and AKR (inbred, nonresponsive). Twelve weekly treatments with 20 mg MC/kg intragastrically were preceded 24 h earlier each week by 150 mg beta-NF/kg i.p. or oil. Mice were killed when moribund or 1 year after start of treatment. During this period the beta-NF-pretreatment greatly reduced mortality due to cancer among the responsive inbred mice, by 100% for the C57BL/6, 89% for the BALB/c, and 65% for the C3H, compared with 50% for the Swiss, 23% for the DBA/2 and 0% for the AKR. There were significant reductions in MC-caused tumor incidences as a result of beta-NF pretreatment for: sarcomas, lymphomas, and forestomach and skin tumors for the C57BL/6 mice; sarcomas, mesotheliomas, and mammary carcinomas for the C3H mice; mesotheliomas for the BALB/c mice; sarcomas and tumors of the skin, forestomach, and lung for the Swiss mice; and lymphomas for the DBA/2 mice. beta-NF pretreatment did not cause an increase in the incidence of any type of tumor. These results are consistent with the conclusion that inducers of mixed function oxygenase activity generally provide protection against tumorigenesis by systemically administered polycyclic aromatic hydrocarbon carcinogens, probably by increasing rate of detoxification.

Age Factors↗