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T J Slaga

Publications and source records attributed to T J Slaga.

At least 253 records · Page 14Linked to original sources
PubMed1977

Benzo(a)pyrene metabolism in mouse epidermis. Analysis by high pressure liquid chromatography and DNA binding.

Mouse epidermal homogenates contain an inducible aryl hydrocarbon hydroxylase (AHH) complex that catalyzes the formation of benzo(a)pyrene-7,8-dihydrodiol from benzo(a)pyrene (BP) as assessed by high pressure liquid chromatography (HPLC). 5,6-Benzoflavone (5,6-BF), 7,8-benzoflavone (7,8-BF) and 17-beta-estradiol decreased and butylated hydroxytoluene (BHT) enhanced oxidative metabolism of BP when added in vitro. Epoxide hydrase activity (hydration of benzo(a)pyrene-4,5-epoxide) (BP-4,5-epoxide) was enhanced by 17-beta-estradiol, 5,6-BF, and 7,8-BF. BHT exhibited no significant effect and 1,2-epoxy-3,3,3-trichloropropane (TCPO) inhibited hydrase activity. The capacity of epidermal homogenates to catalyze the covalent binding of BP to DNA indicated that addition of both 5,6-BF and 7,8-BF decreased binding. BHT and TCPO did not significantly affect DNA-binding.

Animals↗
PubMed1977

The effects of benzoflavones on polycyclic hydrocarbon metabolism and skin tumor initiation.

The effects of benzoflavones on skin tumor initiation by polycyclic hydrocarbons and epidermal aryl hydrocarbon hydroxylase were investigated. 7,8-Benzoflavone (7,8-BF) was found to be a potent inhibitor of the inhibition of skin tumors by 3-methylcholanthrene (MC) as well as 7,12-dimethylbenz(a)anthracene (DMBA). 5,6-Benzoflavone(5,6-BF) inhibited tumor initiation by MC and DMBA, but to a lesser degree than 7,8-BF. Dose-response studies of the capacity of 7,8-BF to inhibit DMBA tumor initiation revealed that 7,8-BF was an effective inhibitor at 2.5 microgram and a maximum inhibition of 90% occurred at 100 microgram of 7,8-FB. The tumor initiating ability of 7-hydroxymethyl-12-methylbenz(a)anthracene (7-OHMe-12MeBA) was not inhibited by 7,8-BF. Epidermal aryl hydrocarbon(benzo(a)pyrene hydroxylase(AHH) was increased by 5,6-BF and either had no effect or was slightly inhibited by 7,8-BF when given either topically or i.p. Both flavones when added directly to the assay tubes inhibited the in vitro epidermal AHH activity from control and MC pretreated mice by greater than 75%. When added in vitro, 7,8-BF and 5,6-BF inhibited epidermally mediated covalent binding of radioactive DMBA and dibenz(a,h)anthracene to DNA by 50% or more. The inhibition of skin tumor initiation by 7,8-BF and 5,6-BF appears to be partially related to its ability to inhibit the formation of electrophilic intermediates.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1977

Skin-tumor-initiating ability of benzo(a)pyrene-7,8-diol-9,10-epoxide (anti) when applied topically in tetrahydrofuran.

The skin-tumor-initiating abilities of various metabolites of benzo(a)pyrene (BP) were determined in mice by using a two-stage system of tumorigenesis. We previously reported that BP-7,8-dihydrodiol (+/- trans) was approximately as potent as BP, suggesting that it may be a proximate carcinogen, but the alleged ultimate carcinogen of BP [BP-7,8-dihydrodiol-9,10-epoxide (anti)] was a weak tumor initiator (Cancer Lett.2: 115, 1976). Because of its high reactivity, the tumor-initiating ability of the BP-7,8-dihydrodiol-9,10-epoxide (anti) was determined by using acetone, benzene, and tetrahydrofuran (THF) as the solvent vehicles. The 'diol-epoxide' of BP was found to be an effective tumor initiator when applied topically in THF. The effectiveness of the various vehicles for the 'diol-epoxide' was as follows: THF greater than benzene greater than acetone; however, acetone was the best solvent for BP tumor initiation. The BP-9,10-dihydrodiol and BP-3-hydroxy were found to be weak tumor initiators. BP-3-hydroxy was also tested for tumor-promoting ability and was found to be inactive in this capacity.

Acetone↗
PubMed1977

The ability of enteric bacteria to catalyze the covalent binding of bile acids and cholesterol to DNA and their in ability to metabolize benzo(a)pyrene to a binding product and to known metabolites.

The capacity of enteric bacteria (E. coli, Salmonella, Pseudomonas, Shigella and Klebsiella) to catalyze the covalent binding of benzo(a)pyrene (BP), cholic acid, deoxycholic acid and cholesterol was investigated. In general, these bacteria were incapable of activating BP to a covalently bound product with calf thymus DNA. Metabolism studies of BP by fluorometric assay failed to indicate any accumulation of BP-3-hydroxy in the incubation medium. Detailed metabolic investigation with high-pressure liquid chromatography indicated that these bacteria did not produce any known metabolites which are formed by mammalian systems. However, radioactivity was detected in all fractions, suggesting that the bacteria were readily metabolizing BP into smaller molecules for energy and carbon sources. Although the enteric bacteria did not metabolize BP into known metabolites, some were capable of activating cholesterol, cholic acid and deoxycholic acid to covalently bound products with DNA. The binding data with cholesterol and bile acids also suggested that the binding process required NADPH as a cofactor because binding level was rather low without NADPH.

Benzopyrenes↗
PubMed1977

Qualitative and quantitative separation of a series of phorbol-ester tumor promoters by high-pressure liquid chromatography.

A high-pressure liquid chromatographic (HPLC) method using a micro-particulate silica column and gradient elution was developed that separated 12-O-tetradecanoylphorbol-13-acetate (TPA) from 20-oxo-TPA; 12-O-tetradecanoylphorbol (TP); 13-O-acetylphorbol (PA), and from the diterpene alcohol, phorbol (P). A series of other phorbol-ester tumor promoters were also separated via HPLC. Spectrophotometric determination at 232 nm allowed detection sensitivities of 0.05 microgram of TPA. When tritiated TPA was applied to mouse skin, the majority of the tritiated product recovered was TPA, indicating only minimal metabolism of TPA and no need for metabolic activation for tumor promotion.

Animals↗
PubMed1977

Dissociation of tumor promoter-stimulated ornithine decarboxylase activity and DNA synthesis in mouse epidermis in vivo and in vitro by fluocinolone acetonide, a tumor-promotion inhibitor.

12-O-Tetradecanoyl phorbol-13-acetate (TPA), a tumor promoter, stimulates DNA synthesis in mouse epidermal cells in vivo and in vitro. This response appears to be mediated through polyamine metabolism because ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17)activity is markedly increased shortly after promoter exposure and this induction varies in magnitude according to dose and promoter potency of a series of phorbol esters. In vitro, exogenous putrescine (0.01-10 mM) results in a dose-related increase and prolongation of promoter-stimulated DNA DNA synthesis, a phenomenon noted in other systems of polyamine-mediated growth stimulation. The anti-inflammatory steroid fluocinolone acetonide (FA), an inhibitor of tumor promotion, prevents TPA stimulation of epidermal proliferation in vivo and in vitro. In vitro, FA most effectively prevents stimulation of DNA synthesis when applied is not required. Paradoxially, FA potentiates the increase in ornithine decarboxylase activity after TPA administeration both in vivo and in vitro. Furthermore, the inhibition of TPA-stimulated DNA synthesis by FA in vitro can be reversed by exogenous putrescine. These results suggestthat FA exerts its antipromotion effect by reducing the sensitivity of the cell to polyamines or by reducing intracellular polyamine levels.

Animals↗
PubMed1977

Effect of trichloropropene oxide on the ability of polyaromatic hydrocarbons and their "K-region" oxides to initiate skin tumors in mice and to bind to DNA in vitro.

The potent epoxide hydrase inhibitor, 1,1,1-trichloro-2,3-propene oxide (TCPO), enhanced the tumor-initiating ability of benzo[alpha]pyrene (BP) and 3-methylcholanthrene (MCA) but had no effect on 9,10-dimethyl-1,2-anthracene (DMBA) initiation in a two-stage system of tumorigenesis in female Charles River CD-1 mice. The tumor-initiating ability of dibenz[alpha,h]-anthracene (DBA) was decreased by prior topical treatment with 10 mumoles of TCPO. The tumor latency period of BP and MCA was decreased by TCPO but had no effect on DMBA or DBA. Topical treatment with 10 mumoles of TCPO did not initiate tumors in a two-stage system in mouse skin nor did it cause any histopathologic changes in the skin. The "K-region" epoxides of BP, DMBA, and MCA were weak tumor initiators when compared to the parent compounds. TCPO only slightly increased or had no effect on the tumor-initiating activity of the above epoxides. Pretreatment with Croton oil 18 hours prior to initiation with BP-4,5-epoxide also slightly enhanced the tumorigenic response in mouse skin. DBA-5,6-epoxide, when tested as a complete carcinogen at high doses (1 mg daily/10 days), was found to be a weak carcinogen but with activity comparable to that of DBA. TCPO only slightly increased the in vitro epidermally mediated covalent binding of the above parent polycyclic hydrocarbons to DNA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1977

Binding of dexamethasone by the subcellular fractions of mouse epidermis and dermis.

The binding of the potent anticarcinogenic agent, dexamethasone, to mouse epidermal and dermal subcellular fractions was investigated. When applied to mouse skin, 3H-labeled dexamethasone remained associated, after extensive dialysis, with epidermal and dermal cytosol, microsomes, microsomes, mitochondria, and chromatin. The specific activity of dexamethasone binding to these fractions was from 2 to 5 times as high in the epidermis as in the dermis. Epidermal chromatin had the highest specific activity fo binding. Dexamethasone was not associated with the cytosol protein receptor which was previously found to specifically bind tumor promoters and polycyclic hydrocarbon carcinogens.

Animals↗
PubMed1977

Inhibition of the tumor-initiating ability of the potent carcinogen 7,12-dimethylbenz(a)anthracene by the weak tumor initiator 1,2,3,4-dibenzanthracene.

ARyl hydrocarbon hydroxylase (AHH) in mouse epidermis was inducible by topical application of several tumor-initiating polycylic aromatic hydrocarbons. The weak tumor initiator 1,2,3,4-dibenazanthracene (1,2,3,4-DBA), at dose level of 200 nmoles, increased AHH activity more than 10-fold over that of the acetone controls at 12 hr after treatment. Administration of the same quantity of the potent initiator 7,12-dimethylbenz(a)anthracene (DMBA) increased AHH activity approximately 4-fold over that of the control at 12 hr after treatment. Simultaneous treatment with 200 or 100 nmoles of DMBA and 1,2,3,4-DBA resulted in AHH activity that was 546 and 732% that of the controls, respectively, 12 hr after treatment: this was less AHH activity than was observed when 1,2,3,4-DBA was administered alone. Doses of 20 nmoles or more of 1,2,3,4-DBA, when given at about the same time as DMBA, effectively inhibited DMBA initiation of skin tumors in a two stage system of tumorigenesis. The results suggest that the weak initiator 1,2,3,4-DBA may program the epidermal AHH system to metabolize the strong carcinogen DMBA to noncarcinogenic intermediate(s).

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1977

The effects of antioxidants on skin tumor initiation and aryl hydrocarbon hydroxylase.

Butylated hydroxytoluene, butylated hydroxyanisole, and vitamins C and E are effective inhibitors of 7,12-dimethylbenz(a)anthracene tumor initiation in a two-stage system of tumorigenesis. These antioxidants did not significantly induce epidermal aryl hydrocarbon [benzo(a)pyrene]hydroxylase, nor did they have any effect when added directly to the in vitro aryl hydrocarbon [benzo(a)pyrene]hydroxylase assay. However, butylated hydroxytolene and butylated hydroxyanisole, when topically to mice, inhibited the in vitro, epidermally mediated, covalent binding of radioactive benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene to DNA. When butylated hydroxytolene and butylated hydroxyanisole were added in vitro, they did not inhibit the epidermally mediated covalent binding of the hydrocarbons to DNA. The inhibition of polycyclic hydrocarbon tumorigenesis by antioxidants may be related to the ability of antioxidants to prevent the in vivo activation of hydrocarbons to carcinogenic epoxides and/or other electrophilic intermediates or may be related to their ability to increase detoxification of the reactive intermediate that requires intact cells to be operational. In any event, the results suggest that the antioxidants have an indirect effect on the epidermal metabolizing system which leads to a decrease in covalent binding to DNA.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1977

The effects of anti-inflammatory agents on skin tumor initiation and aryl hydrocarbon hydroxylase.

The effects of various clinically used anti-inflammatory agents on mouse skin tumorigenesis and aryl hydrocarbon hydroxylase (AHH) were investigated. Oxyphenbutazone, a nonsteroidal anti-inflammatory agent, inhibited 3-methylcholanthrene (MC) tumor initiation but was less effective than the steroidal anti-inflammatory agent, dexamethasone. Oxyphenbutazone was not found to induce AHH activity in mouse epidermis, whereas indomethacin and Seclazone had a slight inducing effect. When these agents were added directly to the in vitro AHH assay, they did not inhibit AHH activity. However, additional experiments have shown a decreased epidermally mediated covalent binding of MC to DNA in vitro when the epidermal homogenates were isolated from mice pretreated with either dexamethasone or oxyphenbutazone and MC at 3 or 12 hr before killing.

Administration, Topical↗
PubMed1977

Effects of antiinflammatory agents on mouse skin tumor promotion, epidermal DNA synthesis, phorbol ester-induced cellular proliferation, and production of plasminogen activator.

The antinflammatory ateroids fluocinoine acetonide, fluocinonide, and fluclorolone acetonide were found to be very effectiveinhibitory agents of mouse skin tumor promotion. These steroids also drastically inhibited epidermal DNA synthesis and epidermal cellular proliferation induced by a phorbal ester tumor promoter. In addition, these compounds were potent inhibitors, of plasminogen activator production in tumor cell cultures. The clinically used non-steroidal antiinflammatory agents oxyphenbutazone, indomethacin, and Seclazone also inhibite tumor promotion but were much less effective. Although these agents are useful against inflammatory disorders in general when given p.o., in our studies they had little effect on inflammation and epidermal cellular proliferation induced by a phorbol ester tumor promoter when given topically. The afore mentioned nonsteroidal antiinflammatory agents also had little effect on epidermal DNA synthesis. Oxyphenbutazone and indomethacin were less potent inhibitors of plasminogen activator production in tumor cells than were the antiinflammatory steroids, and Seclazone produced a negligible inhibition. There is, therefore, a general correlation in the potencies of a series of steroidal antiinflammatory agents for inhibition of tumor promotion and their ability to inhibit plasminogen activator production by tumor cell cultures and epidermal DNA synthesis.

Animals↗
PubMed1977

Marked differences in the tumor-initiating activity of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene on mouse skin.

The ability of optically pure (+)- and (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to initiate skin tumors in mice was determined with a two-stage tumorigenesis system. A single application of 50 to 200 nmoles of (+)- or (-)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to the backs of CD-1 mice followed by twice-weekly applications of 12-O-tetradecanoyl-phorbol-13-acetate revealed that the (-)-enantiomer was 5- to 10-fold more potent than was the (+)-enantiomer as a tumor initiator at the three dosage levels tested. When the tumor-initiating activities of the (+)0 and (-)-enantiomers of trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene were compared to the activity of benzo(a)pyrene at an equimolar dose, the (-)-enantiomer was more active while the (+)-enantiomer was considerably less active. This is the first report of differences in the carcinogenic activity between optical enantiomers.

Animals↗
PubMed1977

Comparison of the tumor-initiating activities of benzo(a)pyrene arene oxides and diol-epoxides.

The ability of arene oxides, and diol epoxides of benzo(a)pyrene to initiate skin tumors in mice was determined by using a two-stage system of tumorigenesis. (+/-)-7beta,8alpha-Dihydroxy-9alpha, 10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was a more effective tumor initiator than was (+/-)-7beta,8alpha-dihydroxy-9beta,10beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene when applied topically to CD-1 mice and then followed by twice-weekly applications of the promotor 12-O-tetradecanoylphorbol-13-acetate. (+/-)-7beta,8alpha-Dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was approximately 20 to 30% as active as benzo(a)pyrene was as a tumor initiator. (+/-)-7beta,8alpha-Dihydroxy-7beta,8beta-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, benzo(a)pyrene, 9,10-oxide, and benzo(a)pyrene 11, 12-oxide, possessed about 1, 2, and 10%, respectively, of the tumor-initiating activity of benzo(a)pyrene.

Animals↗