Metabolism of 2-Aminofluorene by Human Polymorphonuclear Leukocytes: More Evidence for the Association between Inflammation and Cancer

Isola, Vicki J.; Hartman, Tahnee C.; Trumble, Scott J.; Ruzek, Melanie C.; Gentile, James M.

doi:10.2307/3431695

Cited by 3 publications

(3 citation statements)

References 15 publications

(40 reference statements)

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“…(18,28) Additionally, metabolism of AF by venous leukocytes generated undetermined metabolites other than N-OH-AF that appeared to be Salmonella typhimurium strain TA98 mutagens. (33) Currently, there are no studies on the prolonged and persistent existence of T cell anomalies and immunosuppression in AF exposed animals or humans, not to mention, few, if any, detailed studies on components of the immune system. However, Beland et al (1999), and Chen et al (2001), have shown the production of AF-associated DNA adducts in rats fed 2-AAF and 2-N-OH-AAF, respectively.…”

Section: Discussionmentioning

confidence: 99%

Suppression of T Lymphocyte Proliferation to Antigenic and Mitogenic Stimuli by Benzo(α)pyrene and 2-Aminofluorene Metabolites

Lee¹,

Urso²

2007

Immunopharmacology and Immunotoxicology

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Here, we attempt to reveal how 2-aminofluorene (AF), benzo(alpha)pyrene (BP) and their major metabolites affect T-cell responses to antigenic and mitogenic stimuli. P-450-related metabolism of these parent compounds to metabolites seems to precede the observed immunosuppression; therefore, we investigated the influence of alpha-naphthoflavone (P-450 inhibitor) and beta-naphthoflavone (P-450 inducer) on BP and AF immunosuppression. We used proliferative responses to concanavalin A and the allogeneic mixed lymphocyte response as correlates of immunosuppression. We also attempted to correlate DNA-adduction to the extent of observed immunosuppression for AF and BP metabolites. These data show that the pathway to the strongest immunosuppressive agents for polycyclic aromatic hydrocarbons and arylamines are divergent and related to metabolism by P450 enzymes.

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Section: Discussionmentioning

confidence: 99%

Suppression of T Lymphocyte Proliferation to Antigenic and Mitogenic Stimuli by Benzo(α)pyrene and 2-Aminofluorene Metabolites

Lee¹,

Urso²

2007

Immunopharmacology and Immunotoxicology

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“…It is abundant in the azurophilic granules of neutrophils, neutrophil precursors and monocyte/macrophages, and is present at the promyelocyte stage of myeloid maturation (Pember and Kinkade 1983; Subrahmanyam et al 1991). Several environmental chemicals are reported to be activated by MPO to genotoxic metabolites (Arlt et al 2006; Isola et al 1993; Kagan et al 2000; Kalf et al 1991; Lakshmi et al 2000; Shen et al 1990), which could be the basis of selective target organ toxicity and carcinogenicity of certain compounds.…”

Section: Discussionmentioning

confidence: 99%

Investigation of mechanism(s) of DNA damage induced by 4-monochlorobiphenyl (PCB3) metabolites

Xie

Wang

Robertson

et al. 2010

Environment International

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Abstract4-Monochlorobiphenyl (PCB3) is readily converted by xenobiotic-metabolizing enzymes to dihydroxy-metabolites and quinones. The PCB3 hydroquinone (PCB3-HQ; 2-(4'-chlorophenyl)-1,4-hydroquinone) induces chromosome loss in Chinese Hamster V79 cells, whereas the para-quinone (PCB3-pQ; 2-(4'-chlorophenyl)-1,4-benzoquinone) very efficiently induces gene mutations and chromosome breaks. Apparently, each of these two metabolites, which are a redox pair, has a different spectrum of genotoxic effects due to different, metabolite-specific mechanisms. We hypothesized that the HQ requires enzymatic activation by peroxidases with the formation of reactive oxygen species (ROS) as the ultimate genotoxin, whereas the pQ reacts directly with nucleophilic sites in DNA and/or proteins. To examine this hypothesis, we employed two cell lines with different myeloperoxidase (MPO) activities, MPO-rich HL-60 and MPO-deficient Jurkat cells, and measured cytotoxicity, DNA damage (COMET assay), MPO activity, intracellular levels of reactive oxygen species (ROS) and intracellular free -SH groups (monochlorobimane assay, MCB) and free GSH contents (enzyme recycling method) after treatment with PCB3-HQ and PCB3-pQ. We also examined the modulation of these effects by normal/low temperature, pre-treatment with an MPO inhibitor (succinylacetone, SA), or GSH depletion. PCB3-p-Q increased intracellular ROS levels and induced DNA damage in both HL-60 and Jurkat cells at 37 °C and 6 °C, indicating a direct, MPOindependent mode of activity. It also strongly reduced intracellular free -SH groups and GSH levels in normal and GSH-depleted cells. Thus the ROS increase could be caused by reduced protection by GSH or non-enzymatic autoxidation of the resulting PCB3-HQ-GSH adduct. PCB3-HQ did not produce a significant reduction of intracellular GSH in HL-60 cells and reduced intracellular free -SH groups only at the highest concentration tested in GSH depleted cells. Moreover, PCB3-HQ induced DNA damage and ROS production only at 37 °C in HL-60 cells, not at 6 °C or in Jurkat cells at either temperature; no significant DNA damage and ROS production was observed in HL-60 cells at 37 °C if MPO activity was inhibited by SA. These studies show that the effects of PCB3-HQ are enzyme dependent, i.e. PCB3-HQ is oxidized by MPO in HL-60 cells with the generation of ROS and induction of DNA damage. However, this is not the case with the PCB3-pQ, which may produce DNA damage by the reactivity of the quinone with the DNA or nuclear proteins, or possibly by indirectly increasing intracellular ROS levels by GSH depletion. These different modes of action © 2009 Elsevier Ltd. All rights reserved.Corresponding Author: Dr. Gabriele Ludewig, The University of Iowa, Department of Occupational and Environmental Health, 100 Oakdale Campus #124 IREH, Iowa City, IA 52242-5000 Phone: (319) 335-4650, Fax: (319) 335-4290, gabriele-ludewig@uiowa.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our...

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“…It is now associated with numerous diseases, such as cancers (14), infections, wound healing processes (9,10), Alzheimer's disease, etc. In cases of eye diseases, posterior retinal inflammation could lead to posterior retinal pole degenerative lesions which are related to posterior uveitis, high myopia, agerelated macular degeneration and glaucoma (15).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Interleukin-1-Induced Uveitis and Corneal Fibroblast Proliferation by Interleukin-1 Blockers

Chiou¹,

Xuan²,

Liu³

et al. 2000

Journal of Ocular Pharmacology and Therapeutics

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Interleukin-1 (IL-1) is known to trigger induction of inducible nitric oxide synthase (iNOS) to persistently mass produce nitric oxide (NO) to induce various diseases such as cancer, inflammation, Alzheimer's disease and eye diseases, including uveitis, retinopathy, age-related macular degeneration, glaucoma and myopia. Therefore, IL-1 blockers could become an important class of drugs to fight numerous diseases. Among the many compounds studied so far, 1-methyl hydrazino analogs are among the most promising agents to be developed. A minor structural change of 1-methyl hydrazino group into 1-methyl thiosemicarbazido group enhanced their anti-inflammatory activity but reduced their antiproliferation activity on corneal fibroblast cell growth.

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Metabolism of 2-Aminofluorene by Human Polymorphonuclear Leukocytes: More Evidence for the Association between Inflammation and Cancer

Cited by 3 publications

References 15 publications

Suppression of T Lymphocyte Proliferation to Antigenic and Mitogenic Stimuli by Benzo(α)pyrene and 2-Aminofluorene Metabolites

Suppression of T Lymphocyte Proliferation to Antigenic and Mitogenic Stimuli by Benzo(α)pyrene and 2-Aminofluorene Metabolites

Investigation of mechanism(s) of DNA damage induced by 4-monochlorobiphenyl (PCB3) metabolites

Inhibition of Interleukin-1-Induced Uveitis and Corneal Fibroblast Proliferation by Interleukin-1 Blockers

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