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T J Slaga

Publications and source records attributed to T J Slaga.

At least 217 records · Page 12Linked to original sources
PubMed1980

Comparative tumor-initiating activity of methylated benzo(a)pyrene derivatives in mouse skin.

The abilities of various mono and dimethyl derivatives of benzo(a)pyrene (BP) to initiate skin tumors in mice were determined by using a two-stage system of tumorigenesis. 11-Methylbenzo(a)pyrene was found to be approximately 3 times more active as a tumor initiator than was the parent hydrocarbon; 1-methyl benzo(a)pyrene was about twice as active as was BP. Substitution of a methyl group in positions 7, 8, 9, or 10 of BP, which would be involved in a bay-region diol-epoxide, completely counteracts the tumor-initiating ability of BP. 3-, 4-, and 12-methyl-benzo(a)pyrenes and activity equivalent to that of BP, whereas 2-, 5-, and 6-methylbenzo(a)pyrenes, as well as 1,2-, 4,5-, 1,6-, and 3,6-dimethylbenzo(a)pyrenes, were all less active than BP. The concepts of steric inhibition of metabolic activation and stereospecific activation are suggested to explain the tumor-initiating activities of various methylated derivatives.

Animals↗
PubMed1980

Inhibition of skin tumor promotion by retinoic acid and its metabolite 5,6-epoxyretinoic acid.

The ability of 5,6-epoxyretinoic acid, a biologically active metabolites of retinoic acid, to inhibit both the induction of ornithine decarboxylase (ODC) activity and skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA) was evaluated. Application of 5,6-epoxyretinoic acid either concurrently with or 1 hr after each application of TPA to the initiated mouse skin inhibited the formation of skin tumors as effectively as did retinoic acid. 5,6-Dihydroretinoic acid, which is a poor substrate for epoxidation, also inhibited skin tumor promotion. 5,6-Epoxyretinoic acid, 5,6-dihydroretinoic acid, and retinoic acid were equally effective in inhibiting the induction of ODC activity by TPA. Insect juvenile hormones inhibited neither the induction of ODC activity nor skin tumor promotion by TPA. These results indicate that (a) epoxidation of retinoic acid at the 5,6-position is not a rate-limiting modification for the anti-promoting activity of retinoic acid and that (b) inhibition of the induction by TPA of mouse epidermal ODC activity may be a simple test for screening the potential prophylactic activities of new retinoids.

Animals↗
PubMed1979

Effect of the co-carcinogen benzo[e]pyrene on microsome-mediated chemical mutagenesis in Salmonella typhimurium.

Chemical agents that possess the ability to alter tumorigenicity of carcinogens (administered at subthreshold dose) constitute a major health hazard. We have employed the Ames Salmonella assay to examine the effect of co-carcinogenic benzo[e]pyrene (B[e]P) on microsome-mediated chemical mutagenesis. B[e]P enhanced the mutagenic activity induced by 2-acetylaminofluorene (2-AAF) and benzo[a]pyrene (B[a]P) in strains TA1538 and TA98. Enhancement was also noted with N-hydroxy-2-AAF (the proximal metabolite of 2-AAF) but not with an ultimate carcinogenic form (N-acetoxy-2-AAF). These results suggest the use of this approach to detect chemical agents that possess the ability to alter the activity of mutagenic or carcinogenic chemicals.

2-Acetylaminofluorene↗
PubMed1979

Interaction of benzo[alpha]pyrene diol-epoxide with nuclei and isolated chromatin.

Chicken erythrocyte chromatin and nuclei were labeled with benzo[alpha]-pyrene (B[alpha]P) diol-epoxide (anti) and digested with micrococcal nuclease to mono- and dinucleosomes. Analysis of the distribution of the carcinogen showed that the internucleosomal region bound 3-4 times more carcinogen per unit DNA than did nucleosomes. The enhanced binding of the 'ultimate' carcinogen to the internucleosomal region was similar when isolated chromatin or nuclei were used for in vitro labeling. Furthermore, isolation of the histone core proteins, H2A, H2B, H3 and H4, revealed that only 15% of the carcinogen was associated with the histones and that the majority of the carcinogen was bound to chromosomal DNA. Fluorography of purified nucleosomal histones showed that the covalent association of the carcinogen was mainly with histones H3 and H2B.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1979

Effect of weak-, non-, and co-carcinogenic chemicals on 2-acetylaminofluorene-induced mutation in Salmonella typhimurium.

The effects of various weak, non-, and co-carcinogenic chemicals on 2-acetylaminofluorene-induced mutation in Salmonella typhimurium were studied. We found that a single co-mutagen could provide for either enhanced or decreased mutagenesis. A differential effect on mutagenic expression was dependent upon: (1) the type of inducer of S-9 (supernatant from liver homogenate centrifuged at 9000 x g) liver enzymes; (2) the amount of S-9 enzyme preparation employed; and (3) the combined dose of mutagen plus co-mutagen studied. No effect was observed in the absence of S-9. Our data suggest that in S. typhimurium a primary factor in the alteration of mutagenesis by a combination of chemicals is changes in metabolism of the principal mutagen.

2-Acetylaminofluorene↗
PubMed1979

The importance of the "bay region" diol-epoxide in 7,12-dimethylbenz[a]anthracene skin tumor initiation and mutagenesis.

The skin tumor-initiating and V79 mutagenic activities of various derivatives of 7,12-dimethylbenz[a]anthracene (DMBA) were investigated to determine what possible cellular metabolite(s) may be responsible for its carcinogenicity and/or mutagenicity. 1-,2-,3-,4- and 5-hydroxyDMBA were found to be essentially inactive as skin tumor initiators whereas 9- and 10-hydroxyDMBA had weak activity. The (+/-)-trans DMBA 8,9- and 5,6-dihydrodiols were also essentially inactive as skin tumor initiators and (+/-)-DMBA 8beta,9alpha-diol-10alpha-11alpha-epoxide had weak skin tumor initiating activity. All of the above tested derivatives of DMBA were essentially inactive as mutagens in the cell-mediated or direct V79 mutagenesis systems. A methyl or fluoro addition to the 1, 2 or 5 positions almost completely blocked the skin tumor initiating and V79 mutagenic activities of DMBA, whereas a fluoro addition to position 11 did not. From our data we suggest that a 'bay region' diol-epoxide may be important in DMBA carcinogenicity and mutagenicity.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

Covalent binding of polycyclic aromatic hydrocarbons to adenine correlates with tumorigenesis in mouse skin.

Mouse epidermal homogenates were utilized to convert various polycyclic aromatic hydrocarbons to metabolites capable of binding covalently with nucleic acids. Poly(G) showed the highest capacity to bind covalently with the hydrocarbons; however, there was no correlation between binding to poly(G) and mouse skin tumorigenicity. On the other hand, covalent binding to poly(A) correlated well with values obtained for binding to DNA and mouse skin tumorigenicity. The order of binding to poly(A) was; 7,12-dimethylbenza[a]anthracene greater than benzo[a]pyrene greater than dibenz[a,h]anthracene greater than dibenz[a,c]anthracene.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1979

The effects of weak or non-carcinogenic polycyclic hydrocarbons on 7,12-dimethylbenz[a]anthracene and benzo[a]pyrene skin tumor-initiation.

Benzo[e]pyrene (B[e]P) inhibited 7,12-dimethylbenz[a]anthracene (DMBA) skin tumor-initiation in mice by 84%, whereas pyrene and fluoranthene inhibited DMBA initiation by 50 and 34%, respectively. However, B[e]P, pyrene and fluoranthene had either no significant effect or a slight enhancing effect on benzo[a]pyrene (B[a]P) skin tumor-initiation. In addition, B[e]P had essentially no effect on the initiating ability of (+/-)B[a]P-7 beta,8 alpha-diol-9 alpha,10 alpha-epoxide. As a tumor-initiator, B[e]P was found to have very weak activity at a 252 microgram/level (0.4 papillomas/mouse at 40 weeks) and no activity at 100 microgram. When given at a dose of 100 microgram twice weekly, B[e]P induced 2.1 papillomas/mouse at 30 weeks, and 25% of the mice had carcinomas at 40 weeks. However, B[e]P carcinogenic activity is weak when compared to B[a]P, which can induce a comparable tumor response at a dose of 5 microgram twice weekly. When B[e]P was tested as a tumor promoter at a dose of 100 microgram twice weekly after DMBA initiation, it induced 4.5 papillomas/mouse at 30 weeks and a 45% carcinoma incidence at 40 weeks, which was approximately twice as effective as B[e]P alone. The data show that B[e]P is a very weak tumor initiator, a weak complete carcinogen, a moderate tumor promoter, possibly a weak co-tumor-initiator when given with B[a]P, and a potent anit-tumor-initiator when given with DMBA. The anti-tumor initiating and co-tumor-initiating effects of B[e]P appear to be related to its ability to modify the conversion of the tumor initiator into an electrophilic intermediate(s) which are capable of covalently binding to DNA. In addition, B[e]P induced epidermal cellular proliferation which may be related to its promoting ability.

9,10-Dimethyl-1,2-benzanthracene↗