A New Cyclization Reaction Leading to Epoxides of Aromatic Hydrocarbons

Newman, Melvin S.; Blum, Shoshana

doi:10.1021/ja01078a038

Cited by 112 publications

(49 citation statements)

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“…The results in Fig. 3 show that the model number of 22 chromosomes was the same in all eight clones (except possibly clone ED). Therefore, resistance to N2Gua was not caused by the loss of a chromosome.…”

Section: Resultsmentioning

confidence: 82%

Mutagenicity to Mammalian Cells of Epoxides and Other Derivatives of Polycyclic Hydrocarbons

Huberman

Aspiras

Heidelberger

et al. 1971

Proc. Natl. Acad. Sci. U.S.A.

147

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The cytotoxicity and mutagenicity of several polycyclic hydrocarbons and their K-region derivatives were tested in a clone of Chinese hamster cells; the production of clones resistant to 8-azaguanine was used as the marker for mutagenesis. In the series related to benz(a)anthracene, the K-region epoxide was highly mutagenic, and the phenol was less mutagenic; the hydrocarbon and cis and trans-dihydrodiols were not mutagenic. Seven resistant clones were isolated and retained their drug-resistance; three of these could be reverted to the wild type. There was no difference in the chromosome numbers among the parent and mutant clones. The results in the methylcholanthrene series were similar to those for benz(a)anthracene. However, in the dibenz(a,h)-anthracene series, the phenol was more mutagenic than the epoxide. 7-Methylbenz(a)anthracene epoxide and 7-bromomethylbenz(a)anthracene were highly mutagenic, 7-bromomethyl-12-methylbenz(a)anthracene was less mutagenic, and the parent hydrocarbons were inactive. These results demonstrate that metabolic activation of polycyclic hydrocarbon is required for mutagenic activity in mammalian cells.In 1950 it was postulated by Boyland (1) that epoxides are intermediates in the metabolism of polycyclic hydrocarbons. Since then, epoxides have been isolated as intermediates in the microsomal hydroxylation of naphthalene (2) and dibenz(a,h)anthracene (3). Moreover, we have shown that K-region epoxides of polycyclic hydrocarbons react with DNA and proteins (4), and are much more active than the corresponding hydrocarbons, dihydrodiols and phenols at producing malignant transformation in cultures of hamster embryo and mouse prostate cells (5). Therefore, it appears highly probable that epoxides are the metabolically activated and ultimate carcinogenic form of polycyclic hydrocarbons, and in common with other ultimate carcinogens (6), are chemically reactive as electrophiles. An alternative mechanism for the metabolic activation of polycyclic hydrocarbons that contain methyl groups has been proposed, which involves carbonium ion formation on the methyl groups (7,8 Because of this chemical reactivity with DNA, it appeared that epoxides of polycyclic hydrocarbons might possess mutagenic activity. Although in the past there has been a very poor correlation between the mutagenic and carcinogenic activities of a number of potent carcinogens, it was recently demonstrated in this laboratory that the ultimate metabolically active forms of the hepatocarcinogenic aminoazo dyes and acetylaminofluorene are mutagenic to bacteriophage T4, whereas the parent compounds and proximal metabolites are not (9). Thus, it appears that one of the major limitations to the development of correlations between the processes of carcinogenesis and mutagenesis is the fact that the metabolic activation that now appears to be a prerequisite for both processes is not performed by many of the bacterial and phage systems used for the assay of mutagenic activity.Recently, considerable progress has been made in d...

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Section: Resultsmentioning

confidence: 82%

Mutagenicity to Mammalian Cells of Epoxides and Other Derivatives of Polycyclic Hydrocarbons

Huberman

Aspiras

Heidelberger

et al. 1971

Proc. Natl. Acad. Sci. U.S.A.

147

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“…Treatment with 0.5% Me2SO or BA did not give rise to any transformed focus, and MCA was only weakly active in this clone of cells, even at a concentration of 10 ug/ml. On the other hand, treatment of G23 cells for 24 hr with lower concentrations of the K-region epoxides derived from both MCA and BA did result in many piled-up transformed foci (Table 3). The increased transformation at the higher concentrations of epoxides was accompanied by a corresponding decrease in plating efficiency.…”

Section: Resultsmentioning

confidence: 99%

“…500 primary (4-5 days after plating) or secondary (2-3 days after transfer) hamster embryo cells were plated in 60-mm (Falcon) plastic Petri dishes containing a feeder layer of 5 X 104 irradiated rat fibroblasts. 24 hr after plating, acetone solutions of the test compounds were added to the medium in the dishes (final concentration of acetone, 0.5%). The cells were then grown without medium changes for 7-8 days so that the test compounds were present throughout the assay.…”

Section: Cell Culturesmentioning

confidence: 99%

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In Vitro Transformation of Rodent Cells by K-Region Derivatives of Polycyclic Hydrocarbons

Grover

Sims

Huberman

et al. 1971

Proc. Natl. Acad. Sci. U.S.A.

152

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The K-region epoxides and cis-dihydrodiols derived from benz(a)anthracene and from dibenz(a,h)-anthracene have been found to be more active in the production of malignant transformation in hamster embryo cells than the hydrocarbons or the corresponding K-region phenols. The K-region epoxides derived from benz(a)-anthracene and from 3-methylcholanthrene were also active in transforming a clone of ventral prostate cells from the C3H mouse that was not readily transformed by the parent hydrocarbons. The phenols were the most toxic compounds tested but did not transform cells; this confirms that toxicity and transformation are not directly related events. The results obtained support the view that metabolism of polycyclic hydrocarbons precedes toxicity and transformation in rodent cells in culture.

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“…The hydrocarbon-dihydrodiol mixture from the treatment of the mother liquors can be separated on an alumina column eluted with benzene for the hydrocarbon and then with chloroform for the diol. (4) and an equimolar quantity of osmic anhydride, the reaction is completed after 48 h. The hydrocarbon (310 mg) gave 210 mg of fine colorless needles of diol (10) (Formyl-2-phenyl) -6-benzo[c]fiorenone (6) All the attempts to produce oxidative cleavage of the diol 5 by metaperiodate by the described methods (15,16) at different conditions of temperature and pH, have led only to the recovery of the initial product.…”

Section: Oxidation By Osmium Tetroxidementioning

confidence: 99%