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Biomedical subjects

P Sims

Publications and source records attributed to P Sims.

At least 109 records · Page 6Linked to original sources
PubMed1978

The formation of dihydrodiols by the chemical or enzymic oxidation of benz[a] anthracene and 7,12-dimethylbenz[a] anthracene.

When benz[a] anthracene was oxidised in a reaction mixture containing ascorbic acid, ferrous sulphate and EDTA, the non-K-region dihydrodiols, trans-1,2-dihydro-1,2-dihydroxybenz[a] anthracene and trans-3,4-dihydro-3,4-dihydroxybenz[a] anthracene together with small amounts of the 8,9- and 10,11-dihydrodiols were formed. When oxidised in a similar system, 7,12-dimethylbenz[a] anthracene yielded the K-region dihydrodiol, trans-5,6-dihydro-5,6-dihydroxy-7,12-dimethylbenz[a] anthracene and the non-K-region dihydrodiols, trans-3,4-dihydro-3,4-dihydroxy-7,12-dimethylbenz[a] anthracene, trans-8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a] anthracene, trans-10,11-dihydro-10,11-dihydroxy-7,12-dimethylbenz[a] anthracene and a trace of the 1,2-dihydrodiol. The structures and sterochemistry of the dihydrodiols were established by comparisons of their UV spectra and chromatographic characteristics using HPLC with those of authentic compounds or, when no authentic compounds were available, by UV, NMR and mass spectral analysis. An examination by HPLC of the dihydrodiols formed in the metabolism, by rat-liver microsomal fractions, of benz[a] anthracene and 7,12-dimethylbenz[a] anthracene was carried out. The metabolic dihydriols were identified by comparisons of their chromatographic and UV or fluorescence spectral characteristics with compounds of known structures. The principle metabolic dihydriols formed from both benz[a] anthracene and 7,12-dimethylbenz[a] anthracene were the trans-5,6- and trans-8,9-dihydrodiols. The 1,2- and 10,11-dihydrodiols were identified as minor products of the metabolism of benz [a] anthracene and the tentative identification of the trans-3,4-dihydriol as a metabolite was made from fluorescence and chromatographic data. The minor metabolic dihydriols formed from 7,12-dimethylbenz[a] anthracene were the trans-3,4-dihydrodiol and the trans-10,11-dihydriol but the trans-1,2-dihydrodiol was not detected in the present study.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1978

The preparation of dihydrodiols from 7-methylbenz[a]-anthracene.

The products formed when the carcinogenic polycyclic hydrocarbon 7-methylbenz[a] anthracene is oxidized with an ascorbic acid-ferrous sulphate mixture have been investigated. All 5 possible dihydrodiols were formed and the isolation of the 3 non-K-region dihydrodiols, trans-1,2-dihydro-1,2-dihydroxy-7-methylbenz[a]anthracene, trans-3,4-dihydro-3,4-dihydroxy-7-methylbenz[a] anthracene and trans-8,9-dihydro-8,9-dihydroxy-7-methylbenz[a] anthracene is described. The purification of the dihydrodiols was carried out by thin-layer (TLC) followed by preparative high pressure liquid chromatography (HPLC). The ultra-violet, spectral and nuclear magnetic resonance (NMR) characteristics of the dihydrodiols are reported and the data used to assign the proposed structures. An explanation for the unusual preferred conformation which the 8,9-dihydrodiol adopts is advanced.

Animals↗
PubMed1978

The formation of dihydrodiols by chemical or enzymic oxidation of 3-methylcholanthrene.

The chemical oxidation of 3-methylcholanthrene in an ascorbic acid-ferrous sulphate-EDTA reaction mixture gave all five possible dihydrodiols. The structures and stereochemistry of the dihydrodiols were shown by UV, mass and NMR spectral studies and by chemical examination to be cis-2a,3-dihydroxy-3-methylcholanthrene, trans-4,5-dihydro-4,5-dihydroxy-3-methylcholanthrene, trans-7,8-dihydro-7,8-dihydroxy-3-methylcholanthrene, trans-9,10-dihydro-9,10-dihydroxy-3-methylcholanthrene, cis-11,12-dihydro-11,12-dihydroxy-3-methylcholanthrene and trans-11,12-dihydro-11,12-dihydroxy-3-methylcholanthrene. An examination by HPLC of the dihydrodiols formed in the metabolism of 3-methylcholanthrene by rat-liver microsomal preparations showed the presence of trans-4,5-dihydro-4,5-dihydoxy-3-methylcholanthrene, trans-7,8-dihydro-7,8-dihydroxy-3-methylcholanthrene, trans-9,10-dihydro-9,10-dihydroxy-3-methylcholanthrene and trans-11,12-dihydro-11,12-dihydroxy-3-methylcholanthrene, identified by comparison of their UV and chromatographic characteristics with those of authentic standards. Tentative identification of cis- and trans-1,2-dihydroxy-3-methylcholanthrene, cis-2a,3-dihydroxy-3-methylcholanthrene and cis-11,12-dihydro-11,12-dihydroxy-3-methylcholanthrene as metabolites were made from their mobilities using HPLC. A quantitative comparison of the dihydrodiols formed from 3H-labelled 3-methylcholanthrene by microsomal preparations from the livers of normal and 3-methylcholanthrene-treated rats was carried out. trans-9,10-Dihydro-9,10-dihydroxy-3-methylcholanthrene and cis- and trans-1,2-dihydroxy-3-methylcholanthrene were formed when 3-methylcholanthrene was incubated with mouse skin in organ culture.

Animals↗
PubMed1978

Some properties of vicinal diol-epoxides derived from benzo(a)anthracene and benzo(a)pyrene.

The alkylating properties of pairs of syn- and anti-isomers of 2 diol-epoxides derived from benzo(a)pyrene (BP) and of 1 derived from benz(a)anthracene (BA) have been investigated. Of the anti-diol-epoxides, anti-BP 7,8-diol-9,10-oxide was the most reactive compound towards DNA, towards sodium p-nitrothiophenolate in a non-aqueous solvent system, and towards 4-(p-nitrobenzyl)pyridine in aqueous solution; anti-BP 9,10,-diol-7,8-oxide was of intermediate reactivity and anti-BA 8,9-diol-10,11-oxide was least reactive. The syn-diol-epoxides gave unsatisfactory results with DNA and 4-(p-nitrobenzyl)pyridine because of their rapid solvolysis in aqueous solution, but with sodium p-nitrothiophenolate showed the order of reactivity syn-BP 7,8-diol-9,10-oxide greater than syn-BA 8,9-diol-10,11-oxide greater than syn-BP 9,10-diol-7,8-oxide. The products of the reaction between diol-epoxides and nucleic acids were examined by Sephadex LH-20 chromatography followed by high-pressure liquid chromatography (HPLC) and the diol-epoxides were shown to react principally with the guanosine and adenosine moieties of RNA.

Alkylating Agents↗
PubMed1978

Induction of sister-chromatid exchanges in Chinese hamster ovary cells treated in vitro with non-K-region dihydrodiols of 7-methylbenz[a]anthracene and benzo[a]pyrene.

Studies were carried out on the incidence of sister-chromatid exchanges induced in Chinese hamster ovary cells by in vitro treatment with the polycyclic aromatic hydrocarbons 7-methylbenz[a]anthracene and benzo[a]pyrene and with related K-region and non-K-region dihydrodiols. Appreciable increased in the incidence of sister-chromatid exchanges were apparent in cells treated with non-K-region dihydrodiols: the most active compounds were 3,4-dihydro-3,4-dihydroxy-7-methylbenz[a]anthracene and 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene and the effects were dose-dependent. The parent hydrocarbons and the related K-region dihydrodiols induced some sister-chromatid exchanges but they were considerably less active than these two non-K-region diols. The results suggest that this system may usefully be applied to studies aimed at determining which dihydrodiols are important in the metabolic activation of the carcinogenic polycyclic hydrocarbons. These and other results also infer that Chinese hamster ovary cells possess some intrinsic ability to metabolize such compounds in the absence of exogenous activation systems.

Animals↗
PubMed1977

The metabolic activation of 7-methylbenz(a)anthracene: the induction of malignant transformation and mutation in mammalian cells by non-K-region dihydrodiols.

Four different dihydrodiols derived from 7-methylbenz(a)anthracene have been tested, together with the parent hydrocarbon, for their ability to induce the in vitro malignant transformation of mouse M2 fibroblasts and mutations in V79 Chinese hamster cells. In the transformation tests withe the non-K-region dihydrodiols, the 3,4-diol was the most active dihydrodiol tested and the 8,9-diol was also more active than 7-methylbenz(a)anthracene itself; the 1,2-diol showed only slight activity. The K-region dihydrodiol, the 5,6-diol, which cannot be directly metabolized to a vicinal diol-epoxide, was inactive. These differences in biological activity were similar to those apparent in the results from the mutagenicity tests. The data support the general hypothesis that non-I-region dihydrodiols, which can be metabolized to vicinal diol-epoxides, are important in the metabolic activation of the carcinogenic polycyclic hydrocarbons and, when taken together with other results, indicate that 3,4-dihydro-3,4-dihydroxy-7-methylbenz(a)anthracene is most probably involved in the metabolic activation of 7-methylbenz(a)anthracene presumably following conversion into the related diol-epoxide, 3,4-dihydro-3,4-dihydroxy-7-methylbenz(a)anthracene 1,2,-oxide.

Animals↗
PubMed1977

The metabolic activation of 7-methylbenz(a)anthracene in mouse skin.

The metabolism of 7-methylbenz(a)anthracene by rat-liver preparations and by mouse skin has been studied using a combination of thin-layer and high pressure liquid chromatography and all five possible trans-dihydrodiols have been detected as metabolites but in different proportions. The roles of these dihydrodiols and of the related vicinal diol-epoxides in the metabolic activation of 7-methylbenz(a)anthracene in mouse skin has been studied using Sephadex LH-20 column chromatography. The results show that the hydrocarbon-nucleic acid products formed in mouse skin in vivo most probably arise from 3,4-dihydro-3,4-dihydroxy-7-methylbenz(a)anthracene 1,2-oxide which, on the basis of this and other evidence, appears to be the reactive intermediate involved in the metabolic activation of 7-methylbenz(a)anthracene in this tissue.

Animals↗
PubMed1977

Mutagenicity of isomeric diol-epoxides of benzo[a]pyrene and benz[a]anthracene in S. typhimurium TA98 and TA100 and in V79 Chinese hamster cells.

Pairs of isomeric vicinal diol-epoxides derived from benzo[a]pyrene 7,8- and 9,10-dihydrodiols and from benz[a]anthracene 8,9-dihydrodiol were tested for their abilities to revert salmonella typhimurium strains TA98 and TA100 to histidine prototrophy and to induce the formation of 8-azaguanine- or of ouabain-resistant V79 Chinese hamster cells. All six diol-epoxides were active in both bacterial strains, but 7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (the syn isomer) was considerably more mutagenic than the other diol-epoxides. Within the three pairs of stereo-isomeric diol-epoxides, the ratio of the mutagenic potencies of the syn over the related anti isomers varied bothwith the chemical structure and the bacterial strain. The half lives of hydration of these diol-epoxides at pH 7.4 were inversely related to their mutagenic potencies in bacteria. In V79 cells, the two benzo[a]pyrene 7,8-diol 9,10-oxides were mutagenic and the anti isomer was more active than the syn isomer; a reversed order of mutagenic potency with these stereo isomers was observed in S. typhimurium. The other four diol-epoxides were non-mutagenic in V79 cells at the concentrations tested.

Benz(a)Anthracenes↗
PubMed1977

Effect of DNA repair on the cytotoxicity and mutagenicity of polycyclic hydrocarbon derivatives in normal and xeroderma pigmentosum human fibroblasts.

The cytotoxicity of the "K-region" epoxides as well as several other reactive metabolites or chemical derivatives of polycyclic hydrocarbons was compared in normally-repairing human diploid skin fibroblasts and in fibroblasts from a classical xeroderma pigmentosum (XP) patient (XP2BE) whose cells have been shown to carry out excision repair of damage induced in DNA by ultraviolet (UV) radiation at a rate approx. 20% that of normal cells. Each compound tested exhibited a 2- to 3-fold greater cytotoxicity in this XP strain than in the normal strain. To determine whether this difference in survival reflected a difference in the capacity of the strains to repair DNA damage caused by such hydrocarbon derivatives, we compared the cytotoxic effect of several "K-region" epoxides in two additional XP strains, each with a different capacity for repair of UV damage. The ratio of the slopes of the survival curves for each of the XP strains to that of the normal strain, following exposure to each epoxide, was very similar to that which we had previously determined for their respective UV curves, suggesting that human cells repair damage induced in DNA by exposure to hydrocarbon derivatives with the same system used for UV-induced lesions. To determine whether the deficiency in rate of excision repair in this classical XP strain (XP2BE) causes such cells to be abnormally susceptible to mutations induced by "K-region" epoxides of polycyclic hydrocarbons, we compared them with normal cells for the frequency of induced mutations to 8-azaguanine resistance. The XP cells were two to three times more susceptible to mutations induced by the "K-region" epoxide of benzo(a)pyrene (BP), 7,12-dimethyl-benz(a)anthracene (DMBA), and dibenz(a,h)anthracene (DBA). Evidence also was obtained that cells from an XP variant patient are abnormally susceptible to mutations induced by hydrocarbon epoxides and, as is the case following exposure to UV, are abnormally slow in converting low molecular weight DNA, synthesized from a template following exposure to hydrocarbon epoxides, into large-size DNA.

Azaguanine↗
PubMed1977

Malignant transformation and mutagenesis in mammalian cells induced by vicinal diol-epoxides derived from benzo(a)pyrene.

Benzo[a] pyrene and the syn- and anti-isomers of the 7,8-diol 9,10-oxide and of the 9,10-diol 7,8-oxide derived from this hydrocarbon have been tested for their abilities to induce malignant transformation in M2 mouse fibroblasts and mutagenesis in V79 Chinese hamster cells. The anti-isomer of the 7,8-diol 9,10-oxide induced more mutations and transformation than did the other three vicinal diol-epoxides. The two 9,10-diol 7,8-oxides were moderately mutagenic but did not induce any transformation. In contrast, benzo[a]-pyrene induced transformation in M2 fibroblasts but was not mutagenic in the V79 cells.

Animals↗
PubMed1977

The activity of 7-methylbenz(a)anthracene metabolites in an in vitro-in vivo carcinogenicity test using mouse lung tissue.

7-Methylbenz(a)anthracene (7-MBA) and its 5,6-oxide and trans-5,6- and trans-8,9-dihydrodiol were tested for carcinogenic activity in a system in which mouse lung tissue was incubated in the presence of a test compound for 1 h and then implanted into isologous mice. All four compounds gave small yields of adenomas and in addition the 5,6-oxide gave two carcinomas.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1976

Epoxides derived from various polycyclic hydrocarbons as substrates of homogeneous and microsome-bound epoxide hydratase. A general assay and kinetic properties.

A general assay for epoxide hydratase using epoxides derived from polycyclic aromatic hydrocarbons as substrates is described. Addition of dimethylsulphoxide to the incubation mixture after incubation allowed unreacted epoxide and its phenolic by-product to be extracted into light petroleum whilst the product dihydrodiol remained in the aqueous phase. The product was then extracted into ethyl acetate and estimated radiochemically. This assay gave low extraction blanks (0.8-3.8%) when six K-region epoxides of polycyclic hydrocarbons were used, with high recoveries of the corresponding dihydrodiol in the ethyl acetate phase (65-89%). Radiochromatograms demonstrated that all the radioactivity in the ethyl acetate extracts of active incubations above that of boiled enzyme blanks was confined to a single band that always cochromatographed with the authentic trans-dihydrodiol. Using this assay, the kinetic parameters of six K-region epoxides were estimated. In all cases the apparent Km was low (2-5.9 muM). This is about 100-fold lower than the known apparent Km of epoxide hydratase for styrene oxide, an alkene oxide that is widely used as a substrate for epoxide hydratase. The rate of hydration varied with the substrate. Thus the maximum velocity for hydration of phenanthrene 9,10-oxide greater than 7-methylbenz[a]anthracene 5,6-oxide approximately benz[a]anthracene 5,6-oxide approximately benzo[a]pyrene 4,5-oxide greater than 3-methylcholanthrene 11,12-oxide greater than dibenz[a,h] anthracene 5,6-oxide. This relationship between the individual epoxides was found in microsomal fractions from both rat skin and rat liver, although the activity was always much lower in skin microsomes. All six arene oxides derived from polycyclic hydrocarbons were substrates for the homogeneous epoxide hydratase that was isolated from rat liver microsomal fractions using styrene oxide, an alkene oxide, as substrate to follow the purification.

Animals↗
PubMed1976

The involvement of a diol-epoxide in the metabolic activation of benzo(a)pyrene in human bronchial mucosa and in mouse skin.

DNA has been isolated from human bronchial segments that have been treated in short-term organ culture with 3H-labelled benzo (a) pyrene. DNA has also been isolated from mouse skin treated with 3H-labelled samples of benzo (a) pyrene, with the related radioactive 4,5-, 7,8- and 9,10-dihydrodiols and with 3H-3-hydroxybenzo (a) pyrene. Sephadex LH20 column chromatography of hydrolysates of these DNA samples showed that the hydrocarbondeoxyribonucleoside products formed in benzo (a)-pyrene-treated human bronchial mucosa and mouse skin are indistinguishable from those that are formed when 7,8-dihydro-7,8-dihydroxybenzo (a) pyrene 9,10-oxide reacts with DNA in solution. These same hydrocarbon-deoxyribonucleoside products were also found in hydrolysates of DNA from mouse skin treated with 7,8-dihydro-7,8-dihydroxybenzo (a)-pyrene but products of this type were not detected in hydrolysates of DNA following treatment of mouse skin either with the 4,5- or 9,10-dihydrodiols or with 3-hydroxybenzo (a) pyrene. This results show that the metabolic activation of benzo (a) pyrene to a diolepoxide, 7,8-dihydro-7,8-dihydroxybenzo (a) pyrene 9,10-oxide, which reacts with DNA, is the same in human bronchial mucosa, a tissue in which this hydrocarbon is suspected of being carcinogenic, as it is in mouse skin and in hamster embryo cells, two situations in which benzo(a)pyrene is known to induce malignancy.

Animals↗