Polycyclic hydrocarbon activation and metabolism in epithelial cell aggregates prepared from human mammary tissue

Grover, Philip L.; MacNicoll, Alan; Sims, P.; Easty, G. C.; Neville, A. Munro

doi:10.1002/ijc.2910260412

Cited by 21 publications

(10 citation statements)

References 38 publications

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“…11). These results are in agreement with those reported for the major DMBAnucleic acid adducts generated in mouse skin (142), rodent embryo cells in culture (143,144) and in human mammary epithelial cells (145) treated with DMBA. Although our results are consistent with the bay-region theory of polycyclic hydrocarbon carcinogenesis (146) and provide evidence that …”

Section: Dmba-dna Binding By Rat Mammary Epitheliumsupporting

confidence: 92%

Molecular and Cellular Basis of the Mammary Gland Susceptibility to Carcinogenesis

Russo¹,

Tay²,

Ciocca³

et al. 1983

Environmental Health Perspectives

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Mammary carcinomas induced by the administration of 7,12-dimethylbenz(a)anthracene (DMBA) to young virgin rats arise from undifferentiated terminal ductal structures called terminal end buds (TEBs). TEBs that normally differentiate into alveolar buds (ABs) and lobules under the influence of DMBA develop intraductal proliferations which progress to carcinoma. The high susceptibility of the young virgin rat TEBs to neoplastic transformation is due to its large proliferative compartment, with cells cycling every 10 hr, and to a higher 3H-DMBA uptake. Progressive differentiation of TEBs into ABs and lobules or their regression to terminal ducts (TDs) is seen with aging. Complete differentiation of the gland is attained only through pregnancy and lactation. The greater differentiation of the gland is manifested as permanent structural changes, consisting in the disappearance of TEBs and in a diminution of the number of TDs due to their differentiation into ABs and lobules. This greater differentiation results in a diminished or total refractoriness of the gland to the carcinogen because ABs and lobules have a lower proliferative compartment and a longer cell cycle than TEBs and TDs. Cells of parous rats have both in vivo and in vitro a lower DMBA-DNA binding capacity, a lower DNA synthesis and a greater ability to repair DMBA damaged DNA than cells of young virgin rats. The more efficient DNA repair capacity of the parous rat mammary gland is demonstrated by the induction of unscheduled DNA synthesis and a removal of DMBA-DNA adducts.

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Section: Dmba-dna Binding By Rat Mammary Epitheliumsupporting

confidence: 92%

Molecular and Cellular Basis of the Mammary Gland Susceptibility to Carcinogenesis

Russo¹,

Tay²,

Ciocca³

et al. 1983

Environmental Health Perspectives

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“…From the standpoint of carcinogenic potential, the most important fate of BaP appears to be adduct formation between deoxyguanosine and anti BaP diol epoxide, especially the 7R enantiomer (7-10). Recently, binding between metabolites of BaP and nucleosides ofDNA was reported in two human epithelial cell systems, freshly isolated cell aggregates ofmammary epithelial cells (36), and cell strains of keratinocytes (37). The adducts were not positively identified, but both groups (36,37) (38), and more recently, BaP (39).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, binding between metabolites of BaP and nucleosides ofDNA was reported in two human epithelial cell systems, freshly isolated cell aggregates ofmammary epithelial cells (36), and cell strains of keratinocytes (37). The adducts were not positively identified, but both groups (36,37) (38), and more recently, BaP (39). The induction and promotion of these chemically induced adenocarcinomas are enhanced by factors such as high-fat diets, particularly those rich in polyunsaturated fatty acids (40,41), and specific hormonal imbalances (42).…”

Section: Resultsmentioning

confidence: 99%

Metabolism of benzo[a]pyrene by human mammary epithelial cells: toxicity and DNA adduct formation.

Stampfer¹,

Bartholomew²,

Smith³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

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Pure cultures ofhuman breast epithelial cells and of fibroblastic cells in early passage provided the opportunity to ask whether either cell type had the capability for metabolizing chemical carcinogens and, ifso, was the fate ofthe metabolic products compatible with chemical carcinogens being a factor in the initiation of breast cancer in women. For this purpose, cells were exposed to benzo [a]pyrene (BaP), and (i) the influence on growth potential and (ii) the extent, type, and persistence of adducts between the metabolites of BaP and DNA were measured. Compared with fibroblasts, inhibition of growth by epithelial cells was 50-100 times more sensitive to BaP. Because of this differential sensitivity, epithelial cells were exposed to 0.4 FM BaP and fibroblasts were exposed to 4.0 FM BaP in the studies of DNA adduct formation. Separation by high-pressure liquid chromatography of adducts between (±)-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a] The ubiquitous presence of benzo[a]pyrene (BaP) as an environmental pollutant from the incomplete combustion of fossil fuels (1-3) and its potency as a mutagen (2) and carcinogen (3-9) after activation are well documented. The (±)-7,8-dihydroxy-9, 10-epoxy-7,8,9, 10-tetrahydrobenzo[a]pyrenes (BaP-diol epoxides) are the set of metabolites most strongly linked to carcinogenic transformation (3, 4). Of the four isomeric forms of BaP diol epoxide, the 7/3,8a-dihydroxy-9a, lOa-epoxy-7,8,-9, 10-tetrahydrobenzo[a]pyrene (anti BaP diol epoxide), particularly the (7R) or (+) enantiomer, is the most carcinogenic in rodent model systems (7,8), and formation of adducts between this metabolite and deoxyguanosine of DNA predominates in cells susceptible to carcinogenic transformation (9,10 -7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; anti BaP diol epoxide, (+)-7,B,8a-dihydroxy-9a, 8,9,benzo[a]pyrene; syn BaP diol epoxide, (+)-7f3,8a-dihydroxy-9,8,10f-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; HPLC, high-pressure liquid chromatography; bp, base pair(s).

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“…Cultures of A549 cells were set up with BaP, under the conditions described in Table 1. The various classes of metabolite were measured as described by Grover et al (9). As can be seen, the addition of BaP in the adsorbed state resulted in a reduction in the level of water-soluble metabolites in the medium but did not lower the level of covalently bound hydrocarbon; indeed, this increased in one series of cultures.…”

Section: Resultsmentioning

confidence: 99%

Asbestos affects the in vitro uptake and detoxification of aromatic compounds.

Brown¹,

Fleming²,

Knight³

1983

Environ Health Perspect

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A number of mineral dusts were tested for their ability to catalyze the transformation of benzo(a)pyrene from the microcrystalline state into lipid solution. The findings of Lakowicz and his coworkers, that fibrous dusts were more active than nonfibrous dusts, were confirmed. Macromolecular binding metabolites of BaP were formed in A549 cells to a similar extent whether the BaP was added in solution or adsorbed to fibers; however, the level of water-soluble metabolites was lower in cultures treated with adsorbed hydrocarbon. It was found that asbestos can also inhibit the accumulation of 1-naphthyl glucuronide in cultures treated with 1-naphthol. The significance of this in asbestos pathogenesis is briefly discussed.

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Polycyclic hydrocarbon activation and metabolism in epithelial cell aggregates prepared from human mammary tissue

Cited by 21 publications

References 38 publications

Molecular and Cellular Basis of the Mammary Gland Susceptibility to Carcinogenesis

Molecular and Cellular Basis of the Mammary Gland Susceptibility to Carcinogenesis

Metabolism of benzo[a]pyrene by human mammary epithelial cells: toxicity and DNA adduct formation.

Asbestos affects the in vitro uptake and detoxification of aromatic compounds.

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