Tumor-initiating activity of the dihydrodiols of 8-methylbenz-[a]anthracene and 8-hydroxymethylbenz[a]anthracene

Wislocki, Peter G.; Fiorentini, Karen M.; Fu, Peter P.; Chou, Ming W.; Yang, Shen K.; Lu, Anthony Y. H.

doi:10.1093/carcin/2.6.507

Cited by 3 publications

(2 citation statements)

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“…This is important because previous studies in vitro using purified recombinant murine enzymes clearly show that metabolism of DMBA to the mutagenic DMBA-t-3,4-diol occurs preferentially via CYP1B1 (19–21), whereas CYP1A1 metabolism is biased toward nonmutagenic detoxification (fig. S2) (22, 23). DMBA-t-3,4-diol is converted to DMBA-3,4-diol-1,2-epoxide (DMBADE), which is immediately proximal to induction of the Hras codon 61 “signature” point mutation (24, 25).…”

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confidence: 99%

Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma

Modi

Neustadter

Binda

et al. 2012

Science

132

109

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Polyaromatic hydrocarbons (PAHs) are prevalent, potent carcinogens, and 7,12-dimethylbenz[a]anthracene (DMBA) is a model PAH widely used to study tumorigenesis. Mice lacking Langerhans cells (LCs), a signatory epidermal dendritic cell (DC), are protected from cutaneous chemical carcinogenesis, independent of T cell immunity. Investigation of the underlying mechanism revealed that LC-deficient skin was relatively resistant to DMBA-induced DNA damage. LCs efficiently metabolized DMBA to DMBA-trans-3,4-diol, an intermediate proximal to oncogenic Hras mutation, and DMBA-treated LC-deficient skin contained significantly fewer Hras mutations. Moreover, DMBA-trans-3,4-diol application bypassed tumor resistance in LC-deficient mice. Additionally, the genotoxic impact of DMBA on human keratinocytes was significantly increased by prior incubation with human-derived LC. Thus, tissue-associated DC can enhance chemical carcinogenesis via PAH metabolism, highlighting the complex relation between immune cells and carcinogenesis.

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confidence: 99%

Langerhans Cells Facilitate Epithelial DNA Damage and Squamous Cell Carcinoma

Modi

Neustadter

Binda

et al. 2012

Science

132

109

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“…Numerous groups actively synthesized a variety of methylated as well as hydroxylated derivatives of benz(a)anthracene and these were tested for carcinogenic activity (6,(32)(33)(34)(35)(36)(37)(38). Synthetically prepared derivatives of benz(a)anthracene such as 8-methylbenz(a)anthracene have been found to be extremely carcinogenic in the rodent model whereas 9-methybenz(a)anthracene has not been shown to possess carcinogenic activity (39)(40)(41).…”

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confidence: 99%

Bioalkylation of Benz(a)anthracene: Implications for Carcinogenesis

Myers

2007

Polycyclic Aromatic Compounds

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Previous studies on the metabolic activation of unsubstituted polycyclic aromatic hydrocarbons have largely focused on the formation of oxidation products as a result of reaction of the parent hydrocarbon with microsomal enzymes. These products of reaction have included both epoxide as well as a diol epoxide metabolites. In addition, formation of quinones as well as hydroxyl substituted derivatives of various polycyclic aromatic hydrocarbons have been investigated as metabolic endpoints. Several studies have taken place illustrating the formation of these metabolites, as well as the formation of biologically relevant adducts in a variety of animal models as well as cell culture preparations. Although these metabolic products have been widely characterized and studied in a variety of systems, there have been limited studies characterizing the formation of methyl substituted derivatives of unsubstituted aromatic hydrocarbons, and the subsequent formation of hydroxyalkyl derivatives of various compounds. The present study investigates the formation of both alkyl and hydroxyalkyl substituted derivatives of the unsubstituted polycyclic aromatic hydrocarbon benz(a)anthracene in preparations of rat liver cytosolThis article is presented in honor of Dr. James W. Flesher for over 50 years of work in the field of polycyclic aromatic hydrocarbons. His inspiration for the history, chemistry, and structureactivity relationships among this series of compounds continues to be an inspiration for ongoing scientific endeavors. 311 312 S. R. Myers fortified with S-adenosyl-L-methionine. The results demonstrate that methylated derivatives are formed as metabolic products, and that the identity of these products are both the 7-methybenz(a)anthracene and 7,12-dimethylbenz(a)anthracene. These results confirm that aromatic hydrocarbons undergo biological substitution reactions at specific centers of reactivity of the unsubstituted molecule yielding bioalkylated derivatives.

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