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P Sims

Publications and source records attributed to P Sims.

At least 55 records · Page 3Linked to original sources
PubMed1983

Formation of the 1,2-diol as a metabolite of 7,12-dimethylbenz[a]-anthracene by rodent and human skin.

Rodent and human skin maintained in short-term organ culture was treated with 3H-labelled 7,12-dimethylbenz[a]-anthracene. Extracts of the rodent tissue and culture fluid in which either mouse, rat or human skin had been maintained were found to contain radioactive material that possessed the chromatographic characteristics of trans-1,2-dihydro-1,2-dihydroxy-7,12-dimethylbenz[a]anthracene when it was examined in two different h.p.l.c. systems. When the metabolite was treated with hot mineral acid, the two radioactive products formed co-chromatographed with the phenols that were formed when the reference dihydrodiol was similarly treated. Acetylation of the isolated metabolite yielded a single product that had chromatographic properties identical to those of the diacetate of the reference dihydrodiol. Taken together these data show that the 1,2-dihydrodiol of 7,12-dimethylbenz[a]anthracene is formed as a metabolite of this hydrocarbon by rodent and human skin maintained in short-term organ culture.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Preferential binding of polycyclic hydrocarbons to matrix-bound DNA in rat-liver nuclei.

The reactions of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene metabolites and of r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene with the DNA of matrix-bound and released chromatin fractions of rat-liver nuclei have been examined. Qualitatively there were no differences between the DNA-bound metabolites in each fraction but more binding to matrix-bound DNA occurred. Evidence was obtained that the increased binding of hydrocarbon to matrix-bound DNA was not dependent upon the proximity of hydrocarbon-metabolizing enzymes and Sephadex LH20 chromatography showed that the differences between the fractions were not due to contamination of DNA with residual proteins. The conformation of the matrix-bound chromatin may make its DNA more accessible to reactive metabolites than that of released chromatin.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1983

Metabolic activation of chrysene by hamster embryo cells: evidence for the formation of a 'bay-region' diol-epoxide-N2-guanine adduct in RNA.

Ribonucleoside-hydrocarbon adducts present in hydrolysates of RNA isolated from hamster embryo cells treated with 3H-labelled chrysene were examined by chromatography on Sephadex LH20 and by h.p.l.c. on Zorbax ODS. Two adducts formed in cells had chromatographic properties identical to those of two synthetic adducts formed when r-1,t-2-dihydroxy-t-3,4-oxy-1,2,3,4-tetrahydrochrysene (antichrysene 1,2-diol 3,4-oxide) reacted with poly G in vitro. Another adduct formed in cells had chromatographic properties identical to those of a synthetic adduct formed when antichrysene 1,2-diol 3,4-oxide reacted with poly A. In addition to the characterized adducts, other minor adducts were detected whose structures are not known. The structure of the more abundant guanosine--hydrocarbon adduct formed in cells was investigated by determining its pK values and stability in 1 M KOH. The structures of the synthetic guanosine--hydrocarbon adducts were investigated by 1H-n.m.r. spectroscopy. The data show that, in the hydrocarbon--guanosine adducts studied, the hydrocarbon moiety is attached to the exocyclic amino group of guanine.

Animals↗
PubMed1983

Inactivation of a diol-epoxide and a K-region epoxide with high efficiency by glutathione transferase X.

Four glutathione transferases (EC 2.5.1.18), glutathione transferases A, B, and C and a hitherto unknown form, termed X, were purified to apparent homogeneity from rat liver cytosol. They were investigated for their abilities to inactivate two mutagenic epoxides derived from the polycyclic aromatic hydrocarbon benz(a)anthracene, the K-region epoxide benz(a)anthracene 5,6-oxide and the diol-epoxide r-8,t-9-dihydroxy-t-10,11-oxy-8,9,10, 11-tetrahydrobenz(a)anthracene. Mutagenic activity was determined using Salmonella typhimurium his- strain TA100. Glutathione alone had little if any influence on the mutagenicity of the diol-epoxide but significantly decreased the mutagenic effect of the K-region epoxide. This inactivation was enhanced by the addition of glutathione transferases. Both epoxides were inactivated by glutathione in the presence of each of the four enzymes, but with varying efficiencies. Inactivation of the K-region epoxide (in terms of its mutagenicity in the presence of glutathione) required extremely little enzyme, about 1000 times less than for the diol-epoxide. On a molar basis, glutathione transferase X (followed by C greater than A greater than or equal to B) was clearly the most efficient enzyme in inactivating both substrates and also more efficient than were three other purified enzymes (microsomal epoxide hydrolase, cytosolic epoxide hydrolase, and dihydrodiol dehydrogenase) previously investigated in this test system. Taking into account the amounts of enzyme present in rat liver, the glutathione transferases C and X were most effective in inactivating the epoxides examined. Thus, the newly discovered glutathione transferase X appears to be of substantial significance in the inactivation of two structural prototypes of epoxides derived from polycyclic aromatic hydrocarbons, a K-region epoxide and a non-bay-region vicinal diol-epoxide.

Animals↗
PubMed1982

Inactivation of a diol epoxide by dihydrodiol dehydrogenase but not by two epoxide hydrolases.

The mutagenicity of r-8,t-9-dihydroxy-t-10, 11-oxy-8,9,10,11-tetrahydrobenz[a]anthracene (BA-8,9-diol 10, 11-oxide) toward Salmonella typhimurium TA 100 is not decreased by the presence of large amounts of highly purified microsomal or cytosolic epoxide hydrolase. However, highly purified dihydrodiol dehydrogenase inactivates this diol epoxide, which is a major DNA-binding metabolite of benz[a]anthracene. The K-region epoxide, benz[a]anthracene 5,6-oxide (BA 5,6-oxide) is efficiently inactivated by microsomal epoxide hydrolase, is much less readily inactivated by cytosolic epoxide hydrolase, and is not inactivated by dihydrodiol dehydrogenase. This inactivation of a diol epoxide by dihydrodiol dehydrogenase points to a new significance of this enzyme and a new level of control for diol epoxides.

Alcohol Oxidoreductases↗
PubMed1982

Metabolism and activation of benzo[a]pyrene by mouse and rat skin in short-term organ culture and in vivo.

The metabolic activation of BP was examined in mouse and rat skin in vivo and in short-term organ culture. In mouse skin, larger quantities of ether- and water-soluble metabolites were formed and more BP became bound covalently to DNA and protein than in rat skin. Qualitative differences in the formation of dihydrodiol metabolites and of BP-deoxyribonucleoside adducts between mouse and rat skin were also observed. Organ culture techniques may not provide a true model of metabolic activation in vivo because it was found that the covalent binding of BP to DNA and protein was reduced in skin maintained in culture despite an accumulation of dihydrodiol and other ether-soluble metabolites. In addition, the proportions of the syn- and anti-isomers of BP-7,8-diol 9,10-oxide involved in the formation of adducts with deoxyguanosine differed between skin treated in organ culture and in vivo.

Administration, Topical↗
PubMed1982

The metabolism and activation of polycyclic aromatic hydrocarbons in epithelial cell aggregates and fibroblasts prepared from rat mammary tissue.

The metabolism of 7,12-dimethylbenz[a]anthracene (DMBA), benzo[a]pyrene (BP) and benz[a]anthracene (BA) by epithelial cell aggregates and fibroblasts in culture has been investigated using mammary tissue obtained from female Wistar rats. The results show that: (a) both types of mammary cells metabolise all three hydrocarbons into ether- and water-soluble derivatives; (b) the patterns of metabolites produced by epithelial cells and fibroblasts are similar but that fibroblasts form more of the water-soluble materials; (c) the major dihydrodiols formed are the 8,9-dihydrodiols of BA and DMBA and the 7,8- and 9,10-dihydrodiols of BP; (d) all three hydrocarbons are metabolise to form products that bind covalently to protein but only the potent carcinogens BP and DMBA are metabolised to form derivatives that react covalently with DNA; and (e) the chromatographic profiles of the hydrocarbon-deoxyribonucleoside adducts formed in epithelial cells treated with either BP or DMBA are similar to those obtained in analogous experiment with fibroblasts.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

The metabolic activation of chrysene by hamster embryo cells.

The major deoxyribonucleoside--hydrocarbon adducts present in hydrolysates of DNA isolated from hamster embryo cells treated with chrysene were examined by chromatography on Sephadex LH20 and by h.p.l.c. on Zorbax ODS. The results show that both major adducts have chromatographic properties identical to those of adducts formed when r-1,t-2-dihydroxy-t-3,4-oxy-1,2,3,4-tetrahydrochrysene reacts with DNA and provide evidence that metabolic activation of chrysene occurs via the formation of this 'bay-region' diol-epoxide.

Animals↗
PubMed1981

Improved procedure for the anion-exchange isolation of urinary organic acids.

DEAE-Sephadex equilibrated in 0.5 M triethylammonium acetate is suitable for the quantitative isolation of lactonisable organic acids. Mono-, di- and tricarboxylic acids can be eluted sequentially from DEAE-Sephadex by the use of 0.5 M triethylamine, 0.5 M triethylamine--0.1 M acetic acid, and 1.5 M pyridinium acetate.

Carboxylic Acids↗
PubMed1981

New metabolites in isovaleric acidemia.

Two metabolites, 4-hydroxyisovaleric acid and mesaconic acid, have been identified and quantified in the urine of a patient with isovaleric acidemia. These compounds do not appear to have been reported previously as being components of human metabolism. In addition, large quantities of 3-methylbutyrolactone, the lactone of 4-hydroxyisovaleric acid, were observed in the volatile profile obtained by headspace chromatography. The demonstration of 4-hydroxyisovaleric acid supports the contention that urinary methylsuccinic acid seen in patients with isovaleric acidemia has arisen by omega-oxidation of isovaleric acid. The identification of mesaconic acid may indicate that the methylsuccinic acid formed in these patients is subject to further metabolism.

4-Butyrolactone↗
PubMed1981

The metabolic activation of benz[alpha]anthracene in three biological systems.

The 3,4- and 8,9-dihydrodiols of benz[alpha]anthracene (BA) are formed as metabolites of the parent hydrocarbon by rat-liver microsomes, by mouse skin and by hamster embryo cells. In incubations with rat-liver microsomal fractions, only small amounts of the 3,4-dihydrodiol of BA were detected relative to other dihydrodiol metabolites and only small amounts of BA-deoxyribonucleoside adducts derived from the related diol-epoxide, t-3, r-4-dihydroxy-t-1,2-oxy-1,2,3,4-tetrahydrobenz[alpha]anthracene (anti-BA-3,4-diol 1,2-oxide), were detected relative to adducts derived from r-8,t-9-dihydroxy-t-10,11-oxy-8,9,10,11-tetrahydrobenz[alpha]anthracene (anti-BA-8,9-diol 10,11-oxide). However, in studies with mouse skin and hamster embryo cells, larger amounts of free 3,4-dihydrodiol were detected and a larger proportion of the hydrocarbon-deoxyribonucleoside adducts resulted from the reaction of anti-BA-3,4-diol 1,2-oxide with DNA.

Animals↗
PubMed1981

The metabolic and activation of dibenz[a,c]anthracene.

In rat liver microsomal preparations, the 10,11-dihydrodiol of dibenz[a,c]anthracene (DBA) is metabolized to r-10,t-11-dihydroxy-t-12,13-oxy-10,11,12,13-tetrahydrodibenz[a,c]anthracene (anti-DBA 10,11-diol 12,13-oxide), the anti isomer of a non-bay-region diol-epoxide of DBA. When 3H-labelled DBA or trans-10,11-dihydro-10,11-dihydroxydibenz[a,c]anthracene were metabolized in this system in the presence of DNA or when 3H-labelled DBA was added to primary cultures of hamster embryo cells, covalent reactions of hydrocarbon metabolites with DNA occurred. The chromatographic characteristics of the radioactive hydrocarbon-deoxyribonucleoside adducts formed in these reactions were examined using Sephadex LH20 column chromatography and high pressure liquid chromatography. The results showed that whilst some of the radioactive hydrocarbon-deoxyribonucleoside adducts formed were indistinguishable from adducts that were formed when anti-DBA 10,11-diol 12,13-oxide reacted with DNA, other, unidentified adducts, which did not apparently arise from reactions of this diol-epoxide with DNA, were also present. Hydrocarbon-nucleoside adducts were not detected in hydrolysates of nucleic acids that were isolated from mouse skin that had been treated in vivo with DBA.

Animals↗