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Biomedical subjects

J DiGiovanni

Publications and source records attributed to J DiGiovanni.

At least 127 records · Page 7Linked to original sources
PubMed1984

DBA/2 mice are as sensitive as SENCAR mice to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate.

Mice of the inbred strain DBA/2 responded to a two-stage, initiation-promotion tumorigenesis protocol when high initiating doses (400 nmol/mouse) of 7,12-dimethylbenz[a]anthracene were utilized. They also responded when N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was used as the initiating agent. The tumor response in both cases was characterized by a rapid rate of tumor development with the maximal tumor responses reached on or before the 15th week of promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). When DBA/2 mice were compared with SENCAR mice for promotion sensitivity following initiation with MNNG, the two mouse stocks responded with a nearly identical tumor response. C57BL/6 mice were essentially resistant to TPA promotion regardless of the initiator or the dose of initiator used. A preliminary study was conducted to determine how susceptibility to tumor promotion by TPA was inherited in F1 mice derived from DBA/2 (sensitive) and C57BL/6 (resistant) parents. The B6D2F1 mice were as sensitive as the DBA/2 parent, suggesting that susceptibility in these two inbred mouse strains is inherited as an autosomal dominant trait. The results show that these two inbred mouse strains may provide a model system for studying genetic factors controlling susceptibility to phorbol ester skin tumor promotion.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Formation and persistence of DNA, RNA, and protein adducts in mouse skin exposed to pure optical enantiomers of 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyre ne in vivo.

The covalent binding of (+)-anti-benzo(a)pyrene-7,8-diol-9,10-epoxide [(+)-anti-BPDE], the carcinogenic metabolite of benzo(a)pyrene, and its noncarcinogenic (-) enantiomer to macromolecules was investigated in mouse skin in vivo. Levels of the adducts were measured in DNA samples isolated from the epidermis of adult Sencar mice exposed topically to (+)- and (-)-anti-BPDE for 3, 24, and 72 hr. The amount of (+)-anti-BPDE bound to epidermal DNA was approximately 3 times higher than that of the (-) enantiomer at all time points studied, with the highest level of adducts observed after 3 hr exposure. A similar time course of binding was observed in DNA purified from epidermal basal cells which were isolated from mice treated with the two enantiomers. As with the results for isolated DNA samples from whole epidermis, we also observed a 3:1 ratio of binding with (+)- and (-)-anti-BPDE in basal cell DNA. Interestingly, no significant difference in total binding between the (+) and (-) enantiomers could be detected at any time point in RNA and protein isolated from the basal cells. The formation of individual DNA adducts derived from topically applied (+)- or (-)-anti-BPDE was monitored at 3, 24, and 72 hr using high-pressure liquid chromatography. The major DNA adduct (64% of total) formed from (+)-anti-BPDE cochromatographed with marker adducts of N2-[10S-[7R,8S,9R-trihydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene]yl] deoxyguanosine, while other minor adducts also were observed. With the (-)-anti-BPDE, a greater variety of DNA adducts was formed, with only 20 to 30% of the radioactivity present in high-pressure liquid chromatography chromatograms corresponding to the N2-deoxyguanosine adduct. The rate of formation and disappearance of individual adducts derived from both isomers of anti-BPDE was similar over the 72-hr time course. The results suggest that, although differences exist in total binding to DNA between the two enantiomers, they do not appear to be of sufficient magnitude to explain the marked difference in biological activity of (+)- and (-)-anti-BPDE in mouse skin.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1984

Comparison of the metabolic activation of 7, 12-dimethylbenz(a)anthracene by a human hepatoma cell line (HepG2) and low passage hamster embryo cells.

Under similar conditions of cell-mediated mutagenesis, secondary hamster embryo (HE) cells were much more effective than were cells of the human hepatoma cell line, HepG2 , in activating 7, 12-dimethylbenz(a)anthracene (DMBA) to metabolites mutagenic for V79 Chinese hamster cells. At the same dose of DMBA (0.1 microgram/ml), mutation induction (6-thioguanine resistance) with HE cells as activators was about ten times greater than with HepG2 cells as activators. Both cell types rapidly metabolized DMBA. HepG2 cells converted DMBA primarily to water-soluble derivatives that were neither sulfates nor glucuronides, whereas HE cells converted DMBA to a variety of organic solvent-soluble and water-soluble metabolites. The major water-soluble metabolites produced by HE cells were phenol-glucuronides. In HepG2 cells, binding of DMBA to DNA reached a maximum value of 12.1 pmol/mg DNA at 12 hr, whereas in HE cells, binding reached a peak value of 180.7 pmol/mg DNA at 24 hr. Despite this difference in total binding between the two cell types, the pattern of DNA adducts formed was nearly identical. The results indicate that the marked difference in the ability of HepG2 and HE cells to activate DMBA in cell-mediated mutation assays is not due to a lower metabolizing capacity of HepG2 cells for DMBA. Rather, significant differences in the metabolic pathways used by the two cell types lead to a marked reduction in DNA-binding metabolites in one cell type ( HepG2 ) compared to the other (HE).

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

Tumor promoting activity of 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) in female SENCAR mice.

Purified 1,8-dihydroxy-3-methyl-9-anthrone or chrysarobin was found to be an effective skin tumor-promoter in SENCAR mice, although, at the dose used, it was approximately 43-fold less active than 12-O-tetradecanoylphorbol-13-acetate (TPA). When non-promoting doses of chrysarobin were applied 30 min prior to each application of TPA, a marked potentiation in the promoting response to TPA was observed. Chrysarobin will provide a valuable tool for studying the mechanism of action of anthracene-derived mouse skin tumor promoters.

Animals↗
PubMed1983

Enhancement of the skin tumor-initiating activity of polycyclic aromatic hydrocarbons by methyl-substitution at non-benzo 'bay-region' positions.

The effect of substituting a methyl group at the non-benzo 'bay-region' site of several polycyclic aromatic hydrocarbons on skin tumor-initiating activity was determined. A methyl group at this position enhanced the tumor-initiating activity of dibenz[a,h]anthracene, 3-methylcholanthrene and 7-methyldibenz[a,j]anthracene, but not of dibenz[a,c]anthracene. 2,3,7,8-Tetrachlorodibenzo-p-dioxin was an effective inhibitor of skin tumor initiation by 7,14-dimethyldibenz-[a,h]anthracene and 3,6-dimethylcholanthrene. There appears to be a general rule regarding methyl-substituted hydrocarbons: where a 'bay-region' exists in a polycyclic aromatic hydrocarbon molecule, methyl-substitution at the non-benzo 'bay-region' site results in enhanced tumor-initiating activity. The effect of methyl substitution in this position can be most simply explained as due to enhancement of the reactivity of the benzo ring through distortion of the aromatic ring system from planarity. The consequences of this effect are discussed.

Animals↗
PubMed1983

Tumor initiating activity of 9- and 10-fluoro-7,12-dimethylbenz[a]-anthracene (DMBA) and the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on tumor initiation by monofluoro derivatives of DMBA in SENCAR mice.

We have determined the skin tumor initiating activity in SENCAR mice of 6 monofluoro derivatives of 7,12-dimethylbenz[a]anthracene (DMBA). 9-Fluoro-DMBA (9-F-DMBA) was approximately as active, and 10-F-DMBA was more active than the parent hydrocarbon, DMBA. The difference between DMBA and 10-F-DMBA was most dramatic at the highest initiating doses of 10-F-DMBA tested. 4-F-DMBA, which was only weakly active as an initiator, was also tested as a complete carcinogen on mouse skin; after 30 weeks of treatment, 50- and 100-nmol weekly doses failed to elicit papillomas or carcinomas. Animals treated with 50 nmol of DMBA weekly exhibited a 100% papilloma incidence and a 42% carcinoma incidence. Pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) effectively inhibited tumor initiation with all of the monofluoro derivatives of DMBA tested. The ED50 (dose of TCDD producing half-maximal inhibition) for the inhibition of DMBA initiation in SENCAR mice was determined to be 1.8 X 10(-3) micrograms/mouse (5.6 pmol). The results indicate that the introduction of a fluorine atom in ring D of DMBA has no effect (positions 9 and 11) or enhances (position 10) tumor initiating activity. We believe 10-F-DMBA to be the first example of a hydrocarbon with a fluoro substituent giving rise to increased tumor initiating activity. The results also indicate that structural modifications that alter tumor initiating activity do not alter the ability of TCDD to inhibit tumorigenesis by DMBA.

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

Benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene metabolism and DNA adduct formation in primary cultures of hamster epidermal cells.

Primary cultures of hamster epidermal cells exposed to hydrocarbon, 1 microgram/ml, rapidly metabolized [3H]benzo(a)pyrene and [14C]7,12-dimethylbenz(a)anthracene to ethyl acetate:acetone- and water-soluble metabolites. By 24 hr, only 13.6% of the organic solvent-soluble radioactivity recovered in the medium was unchanged [3H]benzo(a)pyrene, and only 5.9% was unchanged [14C]7,12-dimethylbenz(a)anthracene. With both hydrocarbons, the major water-soluble metabolites found extracellularly were conjugated with glucuronic acid; these were primarily phenolic derivatives. Metabolites cochromatographing with 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene or trans-3,4-dihydro-3,4-dihydroxy-7,12-dimethylbenz(a)anthracene were not detectable in high-pressure liquid chromatographic profiles of organic solvent-soluble intracellular and extracellular metabolites. However, analysis of [3H]benzo(a)pyrene: and [3H]7,12-dimethylbenz(a)anthracene: DNA adducts indicated that these putative proximate carcinogenic metabolites were formed in these cells and subsequently metabolized to DNA-binding products. The results suggest that metabolic incompetence may not be an explanation for the relative resistance of the hamster to epidermal carcinogenesis by polycyclic hydrocarbons.

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

Formation of benzo(a)pyrene/DNA adducts and their relationship to tumor initiation in mouse epidermis.

The tumorigenicity of benzo(a)pyrene [B(a)P] applied topically as a skin tumor initiator in Sencar mice and the formation of epidermal B(a)P/deoxyribonucleoside adducts were compared over a similar range of doses (50 to 1600 nmol). The tumor-initiating activity of B(a)P, its covalent binding to mouse epidermal DNA, and the formation of the major hydrocarbon/deoxyribonucleoside adduct showed approximately parallel dose-response curves. The major hydrocarbon/deoxyribonucleoside adduct formed cochromatographed with marker adducts of (N2-(10S-[7R,8S,9R-trihydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene]y) deoxyguanosine while other minor adducts also were observed. The disappearance of DNA-bound products in the epidermis was followed for 21 days after an initiating dose of B(a)P (100 nmol) was applied topically to the mice. The half-lives of the B(a)P/deoxyribonucleoside adducts and the total radioactivity bound to the DNA were 4.5 and 5.5 days, respectively. However, in spite of the loss of measurable DNA-bound material, the tumor yield was unchanged regardless of whether promotion was begun 7 or 21 days after initiation. The results suggest a possible causal relationship between B(a)P/deoxyribonucleoside adduct formation and papilloma formation in mouse skin.

Animals↗
PubMed1983

Mutagenesis in Chinese hamster cells by cyclopenta(a)phenanthrenes activated by a human hepatoma cell line.

The cyclopenta(a)phenanthrene, 15,16-dihydro-11-methyl-cyclopenta(a)phenanthren-17-one, had potent mutagenic activity in cell-mediated mutation assays with V79 Chinese hamster cells as targets, and cells of the human hepatoma line HepG2 as mediators of activation. The compound was inactive when low-passage hamster embryo cells were used as activators. When the mutagenic activity of a series of cyclopenta(a)phenanthrenes was compared in mutation assays with HepG2 cells as activators, there was a good correlation between mutagenic activity in this system and carcinogenic activity in mouse skin in vivo. One exception was a noncarcinogenic compound, which is mutagenic in the Ames' test, and was also mutagenic in the mammalian cell assay.

Animals↗
PubMed1983

Formation of 7-hydroxymethyl-12-methylbenz(a)anthracene-DNA adducts from 7,12-dimethylbenz(a)anthracene in mouse epidermis.

The formation of DNA adducts from [3H]-7-hydroxymethyl-12-methylbenz(a)anthracene (7-OHM-12-MBA) and [3H]-7,12-dimethylbenz(a)anthracene (DMBA) in the epidermis of Sencar mice was analyzed. Comparison of Sephadex LH-20 chromatographic profiles of DNA samples isolated from mice treated with DMBA or 7-OHM-12-MBA suggested that the DMBA-treated animals contained DNA adduct(s) derived from the further metabolism of 7-OHM-12-MBA. Further analysis of DNA samples from DMBA-treated mice by high-pressure liquid chromatography demonstrated the presence of 5 DNA adducts which were chromatographically indistinguishable from the DNA adducts formed in 7-OHM-12-MBA-treated mice. Epidermal homogenates were utilized to catalyze the covalent binding of [3H]DMBA and [3H]-7-OHM-12-MBA to calf thymus DNA in vitro. Under conditions of limiting concentrations of [3H]DMBA, the majority of the DNA adducts formed chromatographed in regions where 7-OHM-12-MBA-DNA adducts eluted. A major DMBA-DNA adduct formed in this in vitro system eluted with the same retention time as did the major 7-OHM-12-MBA-DNA adduct formed in mouse skin in vivo. These results when coupled with the in vivo data suggest that 7-OHM-12-MBA is an intermediate for at least some of the binding of DMBA to epidermal DNA in Sencar mice.

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

Anticarcinogenic and cocarcinogenic effects of benzo[e]pyrene and dibenz[a,c]anthracene on skin tumor initiation by polycyclic hydrocarbons.

In the present study, we have examined the effects of benzo[e]pyrene (B[e]P) and dibenz[a,c]anthracene (DB[a,c]A) on the skin tumor-initiating activities of methylated and non-methylated polycyclic aromatic hydrocarbons (PAH). B[e]P, when applied 5 min prior to initiation with seven different PAH skin carcinogens, effectively inhibited the tumor-initiating activities of 7,12-dimethylbenz[a]anthracene (DMBA) and dibenz[a,h]anthracene (DB[a,h]A) but had little or no effect on the tumor-initiating activities of 3-methyl-cholanthrene (MCA), 7-methylbenz[a]anthracene (7-MBA), 12-methylbenz[a]anthracene (12-MBA), and 5-methyl-chrysene (5-MeC). B[e]P potentiated the tumor-initiating activity of benzo[a]pyrene (B[a]P) by approximately 30%, DB[a,c]A, when applied 5 min prior to initiation, inhibited the tumor-initiating activities of DMBA, MCA, and DB[a,h]A but had little or no effect on the tumor-initiating activities of B[a]P, 7-MBA, 12-MBA, and 5-MeC. DB[a,c]A, when applied 12, 24, or 36 h prior to initiation with B[a]P, which allowed time for induction of epidermal monooxygenase enzymes, inhibited tumor initiation. The covalent binding of DMBA and B[a]P to epidermal DNA was examined under the influence of B[e]P. Doses of 20 and 200 nmol B[e]P given 5 min prior to 10 nmol [3H]DMBA reduced binding to 47 and 22%, respectively, of the control value. In contrast, doses of 200 or 2000 nmol B[e]P given 5 min prior to 200 nmol [3H]B[a]P had little or no effect on total binding. The data indicate that one cannot predict anti and cocarcinogenic effects of B[e]P and DB[a,c]A on the basis of a presence or absence of a methyl substituent. In addition, fundamental differences exist in the processing and metabolism of DMBA and B[a]P by mouse epidermal cells.

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

Tumor-initiating activity of 4-fluoro-7,12-dimethylbenz[a]anthracene and 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene in female SENCAR mice.

We have determined the skin tumor-initiating activity in SENCAR mice of two A-ring derivatives of 7,12-dimethylbenz[a]anthracene (DMBA). 4-Fluoro-7,12-dimethylbenz[a]anthracene at a dose of 200 nmol per mouse exhibited weak activity, producing 0.6 papillopmas per mouse; doses of 10 and 20 nmol per mouse had no activity. A derivative of DMBA with the A-ring reduced, 1,2,3,4-tetrahydro-7,12-dimethylbenz[a]anthracene (1,2,3,4,-H-DMBA), had substantial tumor-initiating activity when compared with the parent hydrocarbon. In one experiment, doses of 10 and 100 nmol per mouse gave rise to 1.6 and 9.5 papillomas per mouse, respectively; similar results were obtained in 3 additional experiments. Although the tumor-initiating activity of 1,2,3,4,-H4-DMBA was approximately one-tenth that of DMBA, this derivative was slightly (17%) more active than benzo[a]pyrene. 1,2,3,4-H4-DMBA was tested for the ability to induce mutations to 6-thioguanine-resistance in Chinese hamster V79 cells. In the absence of feeder cells capable of metabolizing polycyclic hydrocarbons, it was not mutagenic. However, in a cell-mediated mutation assay with secondary hamster embryo cells as activators, this derivative produced mutations in a dose-dependent manner and was approximately one-tenth as active as DMBA. These results indicate that metabolism of DMBA at positions 1-, 3-, 2- and 4- is important for biological activity and that for certain derivatives (i.e., 1,2,3,4-H4-DMBA), alternate pathways of metabolic activation may also be important.

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

Benzo(a)pyrene metabolism in primary cultures of mouse epidermal cells and untransformed and transformed epidermal cell lines.

The metabolism of [3H]benzo(a)pyrene [B(a)P] by cultures of primary mouse epidermal cells and untransformed and transformed epidermal cell lines was investigated. All three cell types effectively metabolized [3H]B(a)P. The major organic solvent-extractable metabolites found intracellularly in primary cultures were trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene and 3-hydroxybenzo(a)pyrene, although quantities of 9-hydroxybenzo(a)pyrene, trans-9,10-dihydro-9,10-dihydroxybenzo(a)pyrene, and quinones also were present. The major organic solvent-soluble metabolites found in the extracellular medium were trans-9,10-dihydro-9,10-dihydroxybenzo(a)pyrene and trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene, with smaller quantities of unconjugated phenols and quinones. The major water-soluble metabolites found in the extracellular medium were conjugated with glucuronic acid [primarily 3-hydroxybenzo(a)pyrene and several quinones]. No sulfate conjugates of [3H]B(a)P metabolites were detected. [3H]B(a)P metabolism was similar in cultures of untransformed and transformed epidermal cell lines but differed from the primary cultures. The major intracellular and extracellular organic solvent-soluble metabolites were diols. Little or no unconjugated phenols were detected. Both the untransformed and transformed epidermal cell lines converted [3H]B(a)P to water-soluble metabolites, primarily glucuronide conjugates. In contrast to the primary cells, a major pathway of trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene metabolism in the untransformed and transformed cell lines was a glucuronide conjugate. Primary mouse epidermal cells provide an important model system for studying factors affecting the activation and detoxification of hydrocarbon carcinogens.

Animals↗
PubMed1980

Biotransformation and bioactivation of 7, 12-dimethylbenz[a]anthracene (7, 12-DMBA).

As the result of rapidly developing technological advances, our understanding of the biotransformation and bioactivation of 7, 12-DMBA has increased markedly in recent years. In terms of the metabolic conversion of this polynuclear aromatic hydrocarbon to reactive mutagen/carcinogens, the "bay region" generalization appears to apply, although the candidacy of a number of other intermediary metabolites as ultimate biologically-active forms still remains viable. Large gaps remain in knowledge concerning the nonoxidative metabolic transformations of 7, 12-DMBA, and these require closing in order to further our understanding of the regulation of mechanics controlling steady-state levels of reactive intermediates. Studies on the photooxidation of the hydrocarbon have allowed a stronger appreciation of its chemical reactivity and instability and promise to help resolve many of the apparently conflicting observations of the past. 7, 12-DMBA remains a highly interesting and valuable tool in investigations of bioactivation processes as they relate to the etiology of several important pathologic conditions, including chemically induced tissue necrosis, mutagenesis, carcinogenesis, teratogenesis, atherogenesis, and, possibly, other pathogenic phenomena as well. It is hoped that this review will serve to benefit research in these areas and hasten the reduction of such pathologic phenomena in our society.

9,10-Dimethyl-1,2-benzanthracene↗