The photodynamic immobilization of Artemia salina nauplii by polycyclic aromatic hydrocarbons and its relationship to carcinogenic activity.
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Animals↗
Biomedical subjects
D Warshawsky
Publications and source records attributed to D Warshawsky.
Specific positions involved in enzyme catalyzed covalent binding of benzo[a]pyrene to poly(G).
Covalent binding of benzo[a]pyrene to poly(G) was studied with the use of a radioactive assay and specifically labeled substrates to define the role of the 1, 3- and 6-positions of the hydrocarbon during this process. Binding was shown to be dependent on microsomes, NADPH, O2 and poly(G). 7, 8-Benzoflavone and 2', 2'-diethylaminoethyl-2, 2-diphenyl valerate were inhibitory w.hereas modulators of epoxide hydrase activity had little effect. 3H and 14C studies suggested a possible loss of one to two protons. Incorporation of [6-3H1]benzo[a]pyrene provided evidence that the 6-position of the hydrocarbon was not metabolized during covalent attachment to poly(G) and, furthermore, results with [1, 3, 6-3H]benzo[a]pyrene suggest that the 1- and 3-positions may not be involved either. After scaling up of the standard assay 20-fold, characterization of the tritiated BaP-poly(G) complex was carried out by hydrolysis and subsequent chromatography. Thin-layer chromatography of the isolated hydrolysis products treated with HCl or alkaline phosphatase indicated that the complex formed between BaP and poly(G) was covalently linked and composed of hydrocarbon-nucleotide(s).
Animals↗
Tritium incorporation at specific positions in benzo(a)pyrene.
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Benzopyrenes↗
Synthesis and characterization of monohydroxylated derivatives of 7H-dibenzo[c,g]carbazole.
The synthesis of several monohydroxylated derivatives of the potent carcinogen 7H-dibenzo[c,g]carbazole (DBC), including 1-hydroxy-7H-dibenzo[c,g]carbazole (1-OH-DBC), 13-c-hydroxydibenzo[c,g]carbazole (13-c-OH-DBC), and 5-hydroxy-7H-dibenzo[c,g]carbazole (5-OH-DBC), is described. 1-OH-DBC was prepared from 8-methoxy-2-tetralone and 2-naphthyl-hydrazine via Fischer indole synthesis followed by boron tribromide demethylation. The rearrangement and hydrolysis reactions to give 13-c-OH-DBC from DBC and benzoyl peroxide are discussed. The preparation and isolation of 5-OH-DBC, by hydrolysis of 5-acetoxy-N-acetyl-DBC, and the formation of its intermediate 5-acetoxy-DBC and its byproduct 6,6'-bis-(5-OH-DBC) are described in detail.
Carbazoles↗
Acetylation of phenolic derivatives of 7H-dibenzo[c,g]carbazole: identification and quantitation of major metabolites by rat liver microsomes.
Acetylation stabilized the phenolic metabolites of 7H-dibenzo[c,g]carbazole (DBC) and made it possible to accumulate greater amounts of metabolites for comprehensive chemical structural elucidation and quantification without the use of radiolabeled DBC. High-resolution mass spectral data and 1H NMR and fluorescence spectra were used to confirm the existence of 5-OH-DBC, 3-OH-DBC, 1-OH-DBC, and the oxidative dimer, 6,6'-bis-(5-OH-DBC), in the acetylated metabolite mixture formed in vitro by 3-methylcholanthrene-induced rat liver microsomes. Using the synthesized acetoxy-DBC derivatives as standards, the HPLC external standard method was employed for quantitation of the major DBC metabolites after acetylation. The quantities of 5-OH-DBC, 3-OH-DBC, 1-OH-DBC, and DBC in the metabolite mixture determined using the external standard method were found to agree with those calculated using the radiometric method. Acetylation is a promising nonradiometric qualitative and quantitative technique for further metabolism studies of DBC and analogues which produce unstable monohydroxylated metabolites.
Acetylation↗
Tissue distribution of DNA adducts of 7H-dibenzo[c,g]carbazole and its derivatives in mice following topical application.
7H-Dibenzo[c,g]carbazole (DBC) is a potent liver and skin carcinogen following topical administration. The objective was to determine the pattern of DBC-DNA adducts produced in both target and nontarget tissues when DBC and its metabolites were applied topically at carcinogenic doses. DBC phenolic derivatives 1-hydroxy-DBC, 2-hydroxy-DBC, 3-hydroxy-DBC, 4-hydroxy-DBC, 5-hydroxy-DBC, 6-hydroxy-DBC, 13-c-hydroxy-DBC, and N-methyl-DBC were applied dermally to Hsd:ICR (Br) mice. Tissues were harvested 24 h later, and DBC-DNA adduct levels were determined by 32P-postlabeling. The levels of DBC-DNA adducts were about 25 times greater in liver than in any other tissue. Total DBC-DNA adducts were seen in skin and lung at about equal levels, while adduct levels in kidney and other tissues were no more than one fourth that of lung and skin. Adduct 6 was the predominant adduct in liver, adducts 2 and 3 were formed preferentially in skin, and adduct 3 was formed preferentially in lung. 3-Hydroxy-DBC and 4-hydroxy-DBC produced higher levels of DNA adducts in skin, lung, and liver than did the parent compound or 2-hydroxy-DBC. DNA adducts were not seen in any tissue for the 1-, 5-, 6-, or 13-c-hydroxy compounds. In addition, hepatic DNA adducts were not seen when the nitrogen of DBC was methylated. In lung and skin, N-methyl-DBC induced DNA adducts at levels comparable to DBC, although the adduct profile in these tissues was different from that of DBC itself.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Topical↗
The effects of a binary mixture of benzo(a)pyrene and 7H-dibenzo(c,g)carbazole on lung tumors and K-ras oncogene mutations in strain A/J mice.
Polycyclic aromatic hydrocarbons (PAH) and N-heterocyclic aromatic hydrocarbons (NHA) are environmental pollutants formed during the incomplete combustion of organic materials. Benzo(a)pyrene (BaP) and 7H-dibenzo(c,g)carbazole (DBC) are well-characterized representatives of the PAH and NHA classes of compunds, respectively. Both are demonstrated carcinogens that frequently co-occur in environmental mixtures. This preliminary study was conducted to investigate the effects of a binary mixture of BaP and DBC on lung carcinogenicity in the strain A/J mouse as manifested by tumor development and mutations in the K-ras gene. Male A/J mice were administered the following single intraperitoneal dose (mg/kg) combinations of BaP and DBC dissolved in a 0.2-mL volume of tricaprylin--10 DBC:10 BaP; 2 DBC:10 BaP; 2 DBC:100 BaP; and 10 DBC: 100 BaP, and each of the compounds alone at the same doses. Mice were sacrificed 8 months after carcinogen treatment and lung tumor multiplicity and K-ras mutations determined (high-dose combination). The combination of DBC and BaP produced fewer tumors than the sum of all tumors produced by each compound acting alone. The frequency of tumors with K-ras mutations was also less in a sample of the 10 DBC:100 BaP treatment group than in the same-dose, single compound-treated animals. The dominant mutations produced by BaP and DBC were expressed in tumors from animals treated with the mixture.
Animals↗
Influence of airborne particulate on the metabolism of benzo[a]pyrene in the isolated perfused lung.
Benzo[a]pyrene (BaP), a ubiquitous potent carcinogen, has been associated with the increased incidence of human bronchiogenic carcinoma in occupational and urban settings. A detailed knowledge of the rate and pattern of metabolite formation and factors affecting their formation is essential for understanding the mechanism of action of BaP in the lung. An isolated perfused New Zealand rabbit lung preparation was used to investigate the effects of a crude airborne particulate mixture on the metabolism of BaP. [14C]BaP with and without crude air particulate (CAP) was administered intratracheally to an isolated perfused lung (IPL) preparation after intratracheal pretreatment of the whole animal with CAP and/or BaP, or intraperitoneal pretreatment of the whole animal with BaP. BaP and its metabolites were extracted from perfusing blood at 6 time points up to 180 min after administration of [14C]BaP to the IPL. BaP and its metabolites were also extracted from lung tissue, washout fluid, aveolar macrophages, 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. Particulate pretreatment of the whole animal or administration of the particulate to the IPL altered BaP metabolism by the perfusing lung. Particulate pretreatment of the whole animal resulted in increases in the total rates of appearance of metabolites of BaP in the blood (ng/g lung . h), while particulate administration to the IPL resulted in decreases in the total rate of appearance of metabolites of BaP in the blood and negated the effects of pretreatments. Coadministration of particulate with BaP to the IPL with and without particulate pretreatment of the whole animal, or BaP administration to the IPL preceded by particulate pretreatment of the whole animal, enhanced dihydrodiol formation and depressed formation of water-soluble materials. This is important because dihydrodiol formation is considered part of the active pathway of BaP carcinogenicity. These data suggest that pulmonary particulate exposure in the presence of BaP results in the initial increased production of dihydrodiols of BaP that may be further metabolized to compounds believed to be the ultimate carcinogenic form(s) of BaP.
Air Pollutants↗