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P Sims

Publications and source records attributed to P Sims.

At least 73 records · Page 4Linked to original sources
PubMed1981

Fluorescence spectra of nucleoside-hydrocarbon adducts formed in mouse skin treated with 7,12-dimethylbenz[a]anthracene.

Hydrolysates of DNA that had been isolated from mouse skin treated with 3H-labelled 7,12-dimethylbenz[a]anthracene (DMBA) were subjected to chromatography on Sephadex LH20 columns and 3H-labelled products that eluted in the region expected for nucleoside-hydrocarbon adducts were purified further by high pressure liquid chromatography (h.p.l.c.). The fluorescence spectra of three major products that were resolved by this method were determined using photoncounting spectrophotofluorimetry. The fluorescence spectra of all three products were anthracene-like and similar to the spectra of nucleoside-hydrocarbon adducts obtained from DNA that was incubated with 3,4-dihydro-3,4-dihydroxy-7,12-dimethylbenz[a]anthracene 1,2-oxide (DMBA-3,4-diol 1,2-oxide). This is consistent with the idea that the metabolic activation of DMBA in mouse skin occurs through the formation of 'bayregion' diol-epoxides in the 1,2,3,4-ring.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Polycyclic hydrocarbon activation and metabolism in epithelial cell aggregates prepared from human mammary tissue.

The metabolism of benz(a)anthracene (BA), 7,12-dimethylbenz(a)anthracene (DMBA) and benzo(a)pyrene (BP) by human mammary epithelial cell aggregates in culture has been investigated using non-neoplastic tissues obtained from eight patients undergoing reduction mammoplasty. All three hydrocarbons were metabolized to water-soluble and organic solvent-soluble products and the latter included both K-region and non-K-region dihydrodiols. The major dihydrodiols detected as metabolites of the parent hydrocarbons were the 8,9-dihydrodiols of BA and DMBA and the 9,10-dihydrodiol of BP. The 1,2-dihydrodiols of BA and DMBA and the 11,12-dihydrodiol of BP were not detected. The hydrocarbons also became bound to the proteins and DNA of the epithelial cells but there were wide differences in the extents of binding occurring with the different hydrocarbons and in the extents of metabolism and binding occurring with tissue preparations from different patients. Some of the hydrocarbon-deoxyribonucleoside adducts formed from DMBA and BP appeared to have arisen through reactions of "bay-region" diol-epoxides with DNA, but only very low levels of reaction with DNA were detected in tissue preparations treated with BA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

The metabolism of a series of polycyclic hydrocarbons by mouse skin maintained in short-term organ culture.

Investigations on the metabolism of 3H-labelled chrysene, benz[a]anthracene, 7-methylbenz[a]anthracene, 7,12-dimethylbenz[a]anthracene, 3-methylcholanthrene, benzo[a]pyrene, dibenz[a,c]anthracene and dibenz[a,h]anthracene by mouse skin maintained in short-term organ culture were carried out. Estimations of the distribution of the metabolites of each hydrocarbon present after 24 h showed that there were wide variations both in the rates at which the hydrocarbons were metabolised and in the amounts of metabolites covalently bound to skin macromolecules. All the hydrocarbons were metabolised to dihydrodiols, which were identified by comparison on high pressure liquid chromatography (HPLC) with the authentic compounds, and these were the same diols as those that were formed in previous experiments with rat-liver microsomal fractions. However, free dihydrodiols represented only relatively small proportions of the total amounts of metabolites formed. All the hydrocarbons yielded dihydrodiols of the type that could give rise to bay-region diol-epoxides, when further metabolised, some of which are thought to be involved in hydrocarbon carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

The metabolic activation of benz[a]anthracene in hamster embryo cells: evidence that diol-epoxides react with guanosine, deoxyguanosine and adenosine in nucleic acids.

The principal nucleoside-hydrocarbon adducts present in hydrolysates of RNA and DNA isolated from hamster embryo cells treated with benz[a]anthracene (BA) were examined by chromatography on Sephadex LH 20 and by high pressure liquid chromatography (HPLC) on Spherisorb 5 ODS. The results extend the previous finding that a non-'bay-region' diol-epoxide, anti-BA-8,9-diol 10,11-oxide (r-8,t-9-dihydroxy-t-10,11-oxy-8,9,10,11-tetrahydrobenz[a] anthracene) is involved in the binding of BA to cellular nucleic acids and show that this diol-epoxide most probably reacts with guanosine and adenosine in RNA and with deoxyguanosine in DNA. The results also show that a 'bay-region' diol-epoxide anti-BA-3,4-diol 1,2-oxide (t-3,-4-dihydroxy-t-1,2-oxy-1,2,3,4-tetrahydrobenz[a]anthracene, which is thought to be involved in the binding of benz[a]anthracene, which is thought to be involved in the binding of benz[a]anthracene to DNA in some situations, reacts mainly with deoxyguanosine.

Adenosine↗
PubMed1980

Mutagenicity of benzo[a]pyrene 7,8-dihydrodiol and 7,12-dimethylbenz[a]anthracene 3,4-dihydrodiol in S. typhimurium mediated by microsomes from rat liver and mouse skin.

The mutagenic activities of trans-7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene (BP 7,8-diol) and of trans-3,4-dihydroxy-7,12-dimethylbenz[a]-anthracene (DMBA 3,4-diol) towards S. typhimurium TA100 were measured in assays that were carried out on a micro-scale in liquid medium in the presence of microsomal fractions prepared from mouse skin or rat liver. In the presence of an NADPH-generating system, microsomal enzymes converted both diols into mutagens that were probably the respective 'bay-region' diol-epoxides. The rate of the enzyme-catalysed conversion of the BP 7,8-diol into mutagens by microsomal preparations from mouse epidermis was similar to that occurring with microsomes from rat liver. Pretreatment of mice by the topical application of benz[a]anthracene (BA) or 7,12-dimethylbenz[a]-anthracene (DMBA) increased the mutagenic activity of BP 7,8-diol mediated by mouse skin microsomal preparations by 2-fold and this was paralleled by a 4-fold increase in epidermal aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) activity. The results are discussed in relation to the high susceptibility of mouse skin to polycyclic aromatic hydrocarbon (PAH) carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

Additional evidence for the involvement of the 3,4-diol 1,2-oxides in the metabolic activation of 7,12-dimethylbenz[a]anthracene in mouse skin.

The role of vicinal diol-epoxides in the metabolic activation of 7,12-dimethylbenz[a]anthracene to intermediates that react with nucleic acids was investigated using Sephadex LH-20 column chromatography and high pressure liquid chromatography. The results show that some of the hydrocarbon-DNA products formed in mouse skin treated in vivo with 7,12-dimethylbenz[a]anthracene arise from the reaction of DNA with 3,4-dihydro-3,4-dihydroxy-7,12-dimethylbenz[a]anthracene 1,2-oxides which, on the basis of this and other evidence, appears to be a biologically-active metabolite of 7,12-dimethylbenz[a]anthracene. However, since other nucleic acid-hydrocarbon adducts were also present that have not been identified as resulting from the reaction of the 3,4-diol 1,2-oxides with DNA, other mechanisms may also be involved in the metabolic activation of 7,12-dimethylbenz[a]anthracene in mouse skin.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

The induction of sister-chromatid exchanges in Chinese hamster ovary cells by some epoxides and phenolic derivatives of benzo[a]pyrene.

The induction of sister-chromatid exchanges in Chinese hamster ovary cells by in vivo treatment with a number of epoxy and phenolic derivatives of the carcinogenic polycyclic hydrocarbon, benzo[a]pyrene, has been investigated. Of the 3 vicinal diol-epoxides tested the anti-isomer of the bay-region 7,8-dihydrodiol-9,10-epoxide was the most active since, when tested at a 10-fold lower concentration, it induced the same number of sister-chromatid exchanges as the corresponding syn-isomer. The anti-isomer of the non-bay-region 9,10-dihydrodiol-7,8-epoxide was much less active than either of the bay-region diolepoxides and its activity was comparable with those of the 2 simple oxides tested, the K-region 4,5- and the non-K-region 7,8-oxides, of benzo[a]pyrene. The 2 phenols tested, 3- and 4-hydroxybenzo[a]pyrene, were only slightly active in inducing sister-chromatid exchanges.

Animals↗
PubMed1980

The involvement of a non-'bay-region' diol-epoxide in the metabolic activation of benza[a]anthracene in hamster embryo cells.

The major hydrocarbon-nucleoside adduct present in hydrolysates of DNA from hamster embryo cells that had been treated with 3H-labelled benz[a]anthracene in culture has been examined by chromatography on Sephadex LH-20 columns and by high-pressure liquid chromatography. The results show that this adduct most probably arises from r-8,t-9-hydroxy-t-10,11-oxy-8,9,10,11-tetrahydrobenz[a]anthracene (anti-BA-8,9.-diol 10,11-oxide). On the basis of this and other evidence, this non-bay-region diol-epoxide appears to be a reactive intermediate involved in the metabolic activation of benz[a]anthracene.

Animals↗
PubMed1980

Metabolic activation of 3-methylcholanthrene in mouse skin: fluorescence spectral evidence indicates the involvement of diol-epoxides formed in the 7,8,9,10-ring.

Hydrolysates of DNA that had been isolated from mouse skin treated with 3H-labelled 3-methylcholanthrene were subjected to chromatography on Sephadex LH20 columns and 3H-labelled products that eluted in the region expected for nucleoside-hydrocarbon adducts were purified further by high pressure liquid chromatography; eight major and one minor products were resolved and their fluorescence spectra were determined using photon-counting spectrophotofluorimetry. The fluorescence spectra of six of the major products are anthracene-like and are similar to the previously-reported spectrum of 7,8,9,10-tetrahydro-3-methylcholanthrene, a result that is consistent with metabolic activation involving diol-epoxide formation in the 7,8,9,10-ring of 3-methylcholanthrene. The fluorescence spectra of the other two major products are also anthracene-like, but their maxima are shifted to longer wavelengths relative to the maxima in the spectrum of 7,8,9,10-tetrahydro-3-methylcholanthrene. The minor product possesses a fluorescence spectrum that is not anthracene-like and that is dissimilar from the spectra of products formed from 3-methylcholanthrene 11,12-oxide.

Animals↗
PubMed1980

The metabolism of the 10,11-dihydrodiol of benz[a]-anthracene to a vicinal diol-epoxide that is not involved in metabolic activation.

Benz[a]anthracene-10,11-diol, a major metabolite of benz[a]anthracene, is metabolized by a rat-liver microsomal system to form anti-BA-10,11-diol 8, 9-oxide (t-10,r-11-dihydroxy-t-8,9-oxy-8,9,10,11 -tetrahydrobenz[a]anthracene) and, to a lesser extent, syn-BA-10,11-diol 8,9-oxide (t-10,r-11-dihydroxy-c-8,9-oxy-8,9,10,11-tetrahydrobenz[a] anthracene). However, when benz[a]anthracene is incubated with DNA in a rat-liver microsomal system, anti-BA-10,11-diol 8,9-oxide does not contribute to the covalent binding of this hydrocarbon to DNA.

Animals↗
PubMed1980

Fluorescence spectral evidence that benzo[a]pyrene is activated by metabolism in mouse skin to a diol-epoxide and a phenol-epoxide.

Hydrolysates of DNA that had been isolated from mouse skin treated with 3H-labelled benzo[a]pyrene were subjected to chromatography on Sephadex LH20. Two major products were eluted in the region expected for deoxyribonucleoside-hydrocarbon adducts and these were purified further by h.p.l.c. The fluorescence emission and excitation spectra of one of the adducts were identical to that of the adduct obtained from DNA that was treated with BP-7,8-diol 9,10-oxide (r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a] pyrene). The fluorescence emission and excitation spectra of the other adducts were identical to the published spectra of 9-OHBP-4,5-diol (4,5-dihydro-4,5,9-trihydroxy-benzo[a]pyrene) and of the deoxyribonucleoside-hydrocarbon adduct obtained from DNA that had been incubated with 9-OHBP (9-hydroxybenzo[a] pyrene) in the presence of a rat-liver microsomal system. The metabolic activation of benzo[a]pyrene in mouse skin, a target tissue for carcinogenesis by this hydrocarbon, thus appears to involve the formation of adducts derived from both BP-7,8-diol 9,10-oxide and 9-OHBP 4,5-oxide (9-hydroxybenzo-[a]pyrene 4,5-oxide), although quantitatively, the adduct derived from 9-OHBP 4,5-oxide is a minor product.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1980

The enzyme-catalysed conversion of anti-benzo[a]pyrene-7,8-diol 9,10-oxide into a glutathione conjugate.

Anti-BP-7,8-diol 9,10-oxide (r-7,t-8-dihydroxy-t-9, 10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene) was converted in the presence of a rat-liver supernatant fraction and glutathione into a water-soluble metabolite that was identified as a glutathione conjugate. The formation of the glutathione conjugate appears to be catalysed by glutathione S-transferases, present in the rat-liver supernatant, because the amount of conjugate formed was reduced considerably when anti-BP-7,8-diol 9,10-oxide was incubated with glutathione either in the absence of the supernatant fraction or in the presence of heat-denatured supernatant fraction.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1980

Metabolic activation of benz[a]anthracene in hamster embryo cells: the structure of a guanosine-anti-BA-8,9-diol 10,11-oxide adduct.

The structures of two guanosine-hydrocarbon adducts prepared from polyG that had been incubated with anti-BA-8,9-diol 10,11-oxide (r-8,t-9-dihydroxy-t-10,11-oxy-8,9,10,11-tetrahydrobenz[a]anthracene) were investigated by examining their H-n.m.r. spectra, their pK values before and after treatment with nitrous acid and their stabilities in 1M KOH. The data show that both of the adducts were formed by reaction between the exocyclic amino group of guanine and the 11-position of the diolepoxide. One of these adducts is indistinguishable from an adduct isolated from hamster embryo cells that had been treated with benz[a]anthracene and that may contribute to the biological activity of this weak carcinogen.

Animals↗