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Biomedical subjects

D Warshawsky

Publications and source records attributed to D Warshawsky.

At least 73 records · Page 4Linked to original sources
PubMed1987

Comparative carcinogenic potencies of 7H-dibenzo[c,g]carbazole, dibenz[a,j]acridine and benzo[a]pyrene in mouse skin.

The relative carcinogenic potencies of three combustion products of fossil fuels, 7H-dibenzo[c,g]carbazole (7H-DB[c,g]C), dibenz[a,j]acridine (DB[a,j]A) and benzo[a] pyrene (B[a]P) were compared using complete carcinogenicity C3H mouse skin bioassays. Both 7H-DB[c,g]C and B[a]P produced tumors in 48 of 50 mice with latency periods of 36.6 and 32.4 weeks, respectively. DB[a,j]A produced tumors in 25 of 50 mice with a latency period of 80 weeks. 7H-DB[c,g]C was found to be as potent a carcinogen as B[a]P when applied to mouse skin. These results have important implications in the determination of relative carcinogenic potencies of complex mixtures.

Acridines↗
PubMed1987

N-methylation reduces the DNA-binding activity of 7H-dibenzo[c,g]carbazole approximately 300-fold in mouse liver but only approximately 2-fold in skin: possible correlation with carcinogenic activity.

N-methyl-dibenzo[c,g]carbazole (MeDBC) lacks the potent hepatocarcinogenic activity in mice characteristic for 7H-dibenzo[c,g]carbazole (DBC), while both compounds are local carcinogens, leading to papilloma and carcinoma formation in skin after topical application. Because DNA binding is considered an essential step in the initiation of chemical carcinogenesis, the DNA adduction by MeDBC was compared with that by DBC in mouse liver and skin via a 32P-postlabeling technique. Both compounds elicited chromatographically similar adducts in liver; however, the extent of total DNA binding of DBC was 343- and 265-fold greater than that of MeDBC 24 h after topical and i.p. administration, respectively, of a 37 mumol/kg dose. In skin, the adduct pattern elicited by either compound after topical application was different from that seen in liver, and three of four adducts derived from MeDBC were chromatographically distinct from those produced by DBC. Quantitative analysis revealed that total adduction in skin by DBC was 2.3-fold higher than by MeDBC. When the adduct levels were compared between liver and skin, topically applied MeDBC bound preferentially to skin versus liver DNA by a factor of 10, while the opposite was true for DBC. These data are in agreement with the carcinogenicity reported for DBC and MeDBC and support the hypothesis that the extent of covalent DNA modification by these compounds is associated with their biological activity. We conclude that an unsubstituted nitrogen is essential for the genotoxic activity of DBC in liver but not skin. The results also demonstrate the potential of the 32P-postlabeling assay in predicting the organotropism of closely related carcinogens.

Administration, Topical↗
PubMed1987

32P-postlabeling analysis of DNA adduction in mice by synthetic metabolites of the environmental carcinogen, 7H-dibenzo[c,g]carbazole: chromatographic evidence for 3-hydroxy-7H-dibenzo[c,g]carbazole being a proximate genotoxicant in liver but not skin.

The DNA adduction by the environmental carcinogen 7H-dibenzo[c,g]carbazole (DBC) and chemically synthesized 2-OH, 3-OH, and 4-OH metabolites of DBC was investigated in liver and skin of female CD-1 mice. After topical application to the skin of 37 mumol/kg of DBC or the phenolic metabolites, DNA adducts were measured by a 32P-post-labeling assay employing carrier-free [gamma-32P]ATP and ATP-deficient conditions. In liver, DBC produced four major and several minor chromatographically distinct adducts of as yet undetermined chemical structure. The adduct pattern elicited by 3-OH-DBC was qualitatively similar to the DBC adduct pattern, while this was not the case for 2-OH-DBC and 4-OH-DBC. On the basis of co-chromatography experiments under various conditions, the DBC and 3-OH-DBC adducts appeared identical, and the total of adduction elicited by these compounds in liver was substantial. Similar results were observed when DBC or 3-OH-DBC were administered i.p. As a major difference between the two compounds, one 3-OH-DBC adduct (no. 3) was 4.4- and 7.0-fold lower than the corresponding DBC adduct after i.p. and topical dosing, respectively. In skin, DBC produced two major adduct fractions after topical application, one of which could be chromatographically resolved into three subcomponents. Prominent adducts produced in skin DNA by each of the three metabolites were different from those elicited by DBC, and the level of adduction by the metabolites was significantly lower than that by DBC. Comparison of the skin and liver DBC-DNA adduct patterns after topical application of DBC showed that only one of the four major chromatographically resolved skin adducts corresponded to a major liver adduct (no. 3), and that total adduction in liver was 13.5-fold higher than in skin. These results suggested that activation of DBC to DNA-binding compounds in liver occurs through at least two pathways with 3-OH-DBC being a proximate carcinogen involved in the formation of most of the adducts; 3-OH-DBC and the other two phenolic metabolites investigated play a minor role, if any, in the formation of DBC-DNA adducts in skin; metabolic activation of DBC to DNA-binding compounds in liver and skin appears to follow pathways that are different in terms of both the chemical nature and the amount of the adducts formed; and DBC and 3-OH-DBC exhibit a strong preference for liver versus skin DNA.

Animals↗
PubMed1985

The metabolism of dibenz[a,j]acridine in the isolated perfused lung.

The metabolism of the carcinogenic N-heterocyclic aromatic, dibenz[a,j]-acridine (DB[a,j]A), was investigated in an isolated perfused rabbit lung preparation. The rate of metabolism of DB[a,j]A was less than the rate of metabolism of 7H-dibenzo[c,g]carbazole (DB[c,g]C) in the untreated and corn oil-pretreated animals. A significantly increased rate of metabolism was observed for DB[a,j]A in benzo[a]pyrene(B[a]P)-pretreated animals. This resulted in marked increases in conjugation and distribution of conjugates and total metabolites in blood and lung. Two major metabolites characterized spectroscopically were assigned as the 3,4-dihydrodiol and a phenol of DB[a,j]A. The results indicate that in the lung DB[a,j]A is metabolized in a manner similar to that of B[a]P.

Acridines↗
PubMed1985

Identification of the 11,12-dihydro-11,12-dihydroxybenzo(a)pyrene as a major metabolite produced by the green alga, Selenastrum capricornutum.

Benzo(a)pyrene metabolites were isolated after incubation of [14C]-benzo(a)pyrene with the green alga, Selenastrum capricornutum. A significant amount of radioactivity chromatographed in the dihydrodiol region which did not coelute with any of the previously identified dihydrodiol metabolites isolated from this system. Following characterization by mass spectrometry, fluorescence spectroscopy, and high pressure liquid chromatography, this metabolite was identified as the cis-11,12-dihydro-11,12-dihydroxybenzo(a)pyrene. This metabolite has not been identified previously as a metabolite formed in a plant system.

Benzo(a)pyrene↗
PubMed1985

Mutagenicity of algal metabolites of benzo(a)pyrene for Salmonella typhimurium.

The metabolism and growth effects of benzo(a)pyrene (BaP) were studied using a freshwater green alga, Selenastrum capricornutum. Algal cultures were incubated under gold light with BaP added at concentrations of 40, 160, 400, and 1,200 micrograms/liter for the periods of 1-4 days. The metabolites and BaP were identified and quantified from ethyl acetate extracts of both algal cells and incubation medium. The ethyl acetate extracts were evaluated for genotoxicity using a micro-volume Salmonella typhimurium forward mutation assay with resistance to 8-azaguanine for selection. This assay detected the presence of small quantities of BaP and was particularly sensitive to the mutagenicity of BaP diols. Of those extracts prepared from algae and medium from cultures exposed to 400 micrograms BaP/liter (10 micrograms/25 ml culture), only algal cell extracts from one day's growth were mutagenic. In cultures exposed to 1,200 micrograms BaP/liter (30 micrograms/25 ml culture), mutagenic materials were produced or persisted in both algae and media throughout the 4-day incubation. The observed mutagenic response can be attributed in part to the presence of unmetabolized BaP or to BaP diols.

Benzo(a)pyrene↗
PubMed1984

The phototoxicity of benzo[a]pyrene in the green alga Selenastrum capricornutum.

The effects of selected polycyclic aromatic hydrocarbons (PAHs) on the growth of the green alga Selenastrum capricornutum in three light regimens were examined. In gold fluorescent light, benzo[a]pyrene (BaP) at 12 mg/liter (48 mumole/liter), benz[a]anthracene (BaA) at 40 mg/liter (175 mumole/liter), anthracene (A) at 40 mg/liter (224 mumole/liter), and 13 metabolites of BaP each at 40 micrograms/liter had no effect on algal growth. In cool-white fluorescent light, 30% inhibition of algal growth occurred with 0.1 mumole/liter BaP, 8.0 mumole/liter BaA, and 40 mumole/liter A. BaP at 0.16 mg/liter (0.64 mumole/liter) totally inhibited growth. BaP concentrations an order of magnitude lower inhibited algal growth in fluorescent blacklight. In cool-white light, 5 of 13 metabolites of BaP (each 40 micrograms/liter) inhibited algal growth: 3,6-quinone; 6-hydroxy; 9-hydroxy; 3-hydroxy; and 1,6-quinone. Based on these results, PAHs and metabolites of BaP are selectively phototoxic to S. capricornutum due to the incident light intensity below 550 nm.

Anthracenes↗
PubMed1984

The pharmacokinetics of benzo[alpha]pyrene in the isolated perfused rabbit lung: the influence of benzo[alpha]pyrene, n-dodecane, particulate, or sulfur dioxide.

The pharmacokinetics of benzo[a]pyrene (BaP) in the isolated perfused rabbit lung (IPL) following pretreatment of the whole animal or simultaneous administration to the IPL with n-dodecane, ferric oxide, crude airborne particulate (CAP), fly ash or sulfur dioxide have been investigated using a one compartment model. The rate constant for the appearance (ka) of BaP in the blood, the clearance of BaP from the blood, and the rate of appearance of BaP metabolites (RAM) were the kinetic parameters determined. BaP entered the blood rapidly with an average half-life of 11 min in experiments in which the IPLs received only BaP on perfusion. The logarithms of the clearances from these experiments were linearly correlated with the RAMs. In these experiments, pretreatment of the whole animal with BaP produced a 48-55-fold increase in BaP clearance while pretreatment with n-dodecane increased the clearance 4-fold in comparison with no pretreatment. Pretreatment with ferric oxide or ferric oxide and BaP increased the clearance by factors of 5.5 and 1.5, respectively, over those of unpretreated and BaP pretreated experiments.

Air Pollutants↗
PubMed1984

The effects of a cocarcinogen, ferric oxide, on the metabolism of benzo[a]pyrene in the isolated perfused lung.

An isolated perfused New Zealand rabbit lung preparation was used to investigate the effects of a cocarcinogen, ferric oxide (Fe2O3), on the metabolism of benzo[a]pyrene (BaP), a ubiquitous potent carcinogen that has been associated with the increased incidence of human bronchiogenic carcinoma in occupational and urban settings. [14C]-BaP was administered intratracheally to an isolated perfused lung (IPL) preparation with and without Fe2O3 after intraperitoneal pretreatment of the whole animal with BaP or intratracheal pretreatment of the whole animal with Fe2O3 and/or BaP. BaP and its metabolites were isolated from serial blood samples up to 180 min after administration of [14C]BaP to the IPL. BaP and its metabolites were also isolated from lung tissue, washout fluid, macrophage, and trachea bronchi at the end of the perfusion at 180 min. Patterns of BaP metabolites were determined by chromatographic techniques and liquid scintillation counting. Fe2O3 pretreatment to the whole animal or administration of Fe2O3 to the IPL altered BaP metabolism by the perfused lung. Fe2O3 pretreatment to the whole animal resulted in an increase in the total rate of appearance of metabolites of BaP in the blood (ng/g lung X h), while Fe2O3 administration to the IPL resulted in a decrease in the total rate of appearance of BaP metabolites in the blood and inhibited the effect of pretreatment. Administration of Fe2O3 with BaP to the IPL with or without Fe2O3 pretreatment to the whole animal, or BaP administration to the IPL preceded by Fe2O3 pretreatment to the whole animal, enhanced dihydrodiol formation and depressed formation of water-soluble metabolites. Since dihydrodiol formation is considered to be the active pathway of BaP metabolism, these data suggest that pulmonary exposure to a known cocarcinogen, Fe2O3, in the presence of BaP results in increased production of dihydrodiols of BaP, which may be further metabolized to the ultimate carcinogenic form(s) of BaP. Therefore, Fe2O3 can enhance the metabolic activation of BaP by the lung, as well as act as a carrier for penetration and retention of BaP in the lung.

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

Mutagenicity of benzo(a)pyrene metabolites generated on the isolated perfused lung following particulate exposure.

The isolated perfused rabbit lung (IPL) is being used to study the effects of particulate exposure on the pulmonary metabolism of benzo(a)pyrene (BaP). Pasturealla-free New Zealand white rabbits were treated intraperitoneally with BaP prior to kill. The isolated lungs were then administered either 14C-labeled BaP alone or BaP plus Fe2O3 or fly ash by intratracheal injection. Rates of appearance of BaP metabolites in the perfusing blood were determined. The extent of metabolism, distribution of metabolites, and types of metabolites produced were quantified for various lung tissue types by high-performance liquid chromatography and liquid scintillation spectrometry. Procedures were developed to apply the Salmonella/microsome test in the assay of mutagenicity of lung tissue and blood extracts as an indicator of their biologic activity. With few exceptions, blood extracts from IPL receiving BaP only were not mutagenic. Lung, trachea-bronchi, and macrophage extracts, by contrast, were mutagenic. A part of this activity could be attributed to BaP metabolites rather than to parent compound remaining in extracts. When lungs were exposed to Fe2O3 or to fly ash, only macrophage extracts were consistently mutagenic. This activity was due to significant amounts of unmetabolized BaP.

Animals↗
PubMed1982

Evaluation of coal liquefaction technologies by Salmonella mutagenesis.

Coal liquefaction materials made by two processes were found to be mutagenic in the Salmonella/microsome assay. Data from this type of in vitro assay can be used in the toxicological assessment of these processes. Such evaluations of the health and environmental impacts of technologies would aid in the development of alternate energy sources.

Animals↗
PubMed1981

Mutagenicity of products from coal gasification and liquefaction in the Salmonella/microsome assay.

As a first step in the assessment of their possible bio-effects, coal-related materials were tested for mutagenicity in the Salmonella/microsome assay. Of three coal gasification by-products tested, only a tar was mutagenic for any of four Salmonella strains. The following liquefaction materials were mutagenic for strains TA1538, TA98, and/or TA100: A liquefaction vehicle oil and coal hydrogenation filtered liquid, separated bottoms, vacuum overhead, and vacuum bottoms. Neither powdered coal nor water produced as a by-product of the hydrogenation process was positive in the Salmonella test. No coal-related material was mutagenic for the missense mutant TA1535 or for any strain in the absence of metabolic activation provided by rat hepatic homogenates (S9). In all but one instance Aroclor 1254-induced S9 provided the maximum activation for mutagenesis. Fractionation of all samples was undertaken by serial extraction with organic solvents of increasing polarity (hexane, toluene, methylene chloride, acetonitrile). Highly mutagenic materials were found in fractions of the hydrogenation filtered liquid, vacuum overhead, and vacuum bottoms. Thus far non-mutagenic samples have not yielded mutagenic components upon fractionation.

Animals↗
PubMed1981

The metabolism of 7H-dibenzo[c,g]carbazole, an N-heterocyclic aromatic, in the isolated perfused lung.

The metabolism of a carcinogenic N-heterocyclic aromatic, 7H-dibenzo[c,g]carbazole, was investigated in an isolated perfused rabbit lung preparation in a rat liver microsomes. A major metabolite produced in both preparation is the 7-hydroxydibenzo[c,g]carbazole. A substantial percentage of this metabolite is found in the tracheabronchi, which would be consistent with the high incidence of respiratory tract tumors due to dibenzo[c,g]carbazole.

Animals↗
PubMed1981

Influence of sulfur dioxide on metabolism and distribution of benzo[a]pyrene in isolated perfused rabbit lung.

An isolated perfused lung [IPL) preparation was used to investigate the effects of SO2 (1-2 ppm) on the metabolism of benzo[a]pyrene (BaP), a ubiquitous potent carcinogen that has been associated with the increased incidence of a human bronchiogenic carcinoma in occupational and urban populations. [14C]BaP, with and without crude air particulate (CAP), was administered intratracheally to the IPL in conjunction with SO2 or after pretreatment of the whole animal with SO2. Metabolites were isolated from serial blood samples up to 3 h after the administration of [14C]BaP to the IPL. Metabolites were also isolated from lung tissue, washout fluid, macrophage, and trachea and bronchi at the end of the perfusion at 180 min. Patterns of BaP metabolites were determined by thin-layer and high-performance liquid chromatography and scintillation counting. SO2 given in conjunction with BaP on the IPL or given to the whole animal followed by BaP on the IPL, in comparison with BaP only on the IPL, resulted in a twofold increase in the total rate of appearance of metabolites of BaP in the blood with changes in the metabolic pattern. SO2 given in conjunction with BaP and CAP on the IPL, in comparison with BaP plus SO2 on the IPL, resulted in a threefold decrease in the total rate of appearance of metabolites of BaP in the blood with changes in the metabolic pattern.

Animals↗
PubMed1977

Characterization of a photoproduct of 7,12-dimethylbenz[alpha]anthracene and its effects on chick-embryo cells in culture.

A common impurity of 7,12-dimethylbenz[alpha]anthracene was more effective than 7,12-dimethylbenz[alpha]anthracene in inducing morphological alterations, and in causing an increase in glucose uptake, DNA synthesis and cell number in chick-embryo fibroblasts. Gradual morphological transformation follows the increase in DNA synthesis after 2 days when either primary or secondary cultures are treated with 3 microgram of the compound/ml. The compound, isolated from 7,12-dimethylbenz[alpha]anthracene by alumina column chromatography, was characterized by t.l.c., mass spectroscopy, carbon-hydrogen analysis, u.v. and nuclear-magnetic-resonance spectroscopy and thermal decomposition. It was the photo-oxidation product of 7,12-dimethylbenz[alpha]anthracene, 7,12-epidioxy-7,12-dimethylbenz[alpha]anthracene. It is suggested that some of the biological effects observed after treatment of cultures with 7,12-dimethylbenz[alpha]anthracene may be due in part to the presence of the photo-oxidation product.

9,10-Dimethyl-1,2-benzanthracene↗