Comparative tumorigenicity in newborn mice of chrysene- and 5-alkylchrysene-1,2-diol-3,4-epoxides

Amin, S. G.; Misra, Bijaya; Braley, Joanne; Hecht, Stephen S.

doi:10.1016/0304-3835(91)90032-d

Cited by 10 publications

(14 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The carcinogenicity of PAHs has been clearly shown in both epidemiological studies and bioassays with laboratory animals ( International Agency for Research on Cancer, 1983 ). The metabolite (±)-anti-5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE), one important member of PAH, has been found to be strongly carcinogenic ( Hecht et al, 1974 ; Amin et al, 1991 ; You et al, 1994 ; Nesnow et al, 1998 ). Similar to (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), 5-MCDE is the in vivo epoxide metabolite of its parent compound 5-methylchrysene, which has been identified in tobacco and marijuana smoke as well as gasoline and diesel engine exhaust ( Hecht et al, 1974 ; Lee et al, 1976 ; Grimmer, 1977 ).…”

Section: Introductionmentioning

confidence: 99%

PI-3K and Akt are mediators of AP-1 induction by 5-MCDE in mouse epidermal Cl41 cells

Chen

Tang

et al. 2004

The Journal of Cell Biology

View full text Add to dashboard Cite

5-Methylchrysene has been found to be a complete carcinogen in laboratory animals. However, the tumor promotion effects of (±)-anti-5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE) remain unclear. In the present work, we found that 5-MCDE induced marked activator protein-1 (AP-1) activation in Cl41 cells. 5-MCDE also induced a marked activation of phosphatidylinositol 3-kinase (PI-3K). Inhibition of PI-3K impaired 5-MCDE–induced AP-1 transactivation, suggesting that PI-3K is an upstream kinase involved in AP-1 activation by 5-MCDE. Furthermore, we found that Akt is a PI-3K downstream mediator for 5-MCDE–induced AP-1 transactivation, whereas another PI-3K downstream kinase, p70S6K, was not involved in AP-1 activation by 5-MCDE. Moreover, inhibition of Akt activation blocked 5-MCDE–induced activation of extracellular signal–regulated protein kinases (ERKs) and c-Jun NH2-terminal kinases (JNKs), whereas it did not affect p38K activation. Consistently, overexpression of a dominant-negative mutant of ERK2 or JNK1 blocked the AP-1 activation by 5-MCDE. These results demonstrate that 5-MCDE is able to induce AP-1 activation, and the AP-1 induction is specifically through a PI-3K/Akt–dependent and p70S6K-independent pathway.

show abstract

Section: Introductionmentioning

confidence: 99%

PI-3K and Akt are mediators of AP-1 induction by 5-MCDE in mouse epidermal Cl41 cells

Chen

Tang

et al. 2004

The Journal of Cell Biology

View full text Add to dashboard Cite

show abstract

“…Chrysene is a relatively well-known PAH that has been characterized as a carcinogenic agent, and 5-methylchrysene has received attention for its genotoxicity and carcinogenicity in mouse skin tumor models. 26,27 Less is known about the toxicological properties of the other methylated chrysenes. Thus, these compounds were compared for various activities described here.…”

Section: Discussionmentioning

confidence: 99%

Aryl hydrocarbon receptor signaling, toxicity, and gene expression responses to mono‐methylchrysenes

Alqassim

Wilson

Wickliffe

et al. 2019

Environmental Toxicology

View full text Add to dashboard Cite

Polycyclic aromatic hydrocarbons (PAHs) comprise a large family of toxic compounds that come from natural and anthropogenic sources. Chrysene is a PAH with multiple effects, but the toxic potentials of mono‐methylchrysenes are less characterized. A comparison of chrysene and six mono‐methylchrysenes was performed using assays for cytotoxicity, human aryl hydrocarbon receptor (AhR) reporter gene signaling, and AhR‐regulated target gene and protein expression. Sulforhodamine B and trypan blue dye binding assays revealed these chrysenes to be similar in their cytotoxic effects on HepG2 cells. A yeast‐based reporter assay detecting human AhR‐mediated gene expression identified 4‐methylchrysene as being six times more potent and 5‐methylchrysene about one‐third as potent as chrysene. Other methylchrysenes were more similar to chrysene in the ability to act as AhR ligands. The mono‐methylchrysenes all strongly induced CYP1A1 mRNA and protein and moderately induced CYP1B1 expression in HepG2 cells. Levels of CYP1A2 mRNA were induced at higher concentrations of the chrysenes, but protein expression was not significantly altered. The PCR‐based gene expression and immunoblotting analyses indicated induced expression differences across the chrysene members were similar to each other. Overall, the effects of methylated chrysenes were comparable to unsubstituted chrysene, suggesting members of this group may be considered approximately equivalent in their effects. © 2019 Wiley Periodicals, Inc.

show abstract

“…The substrate for the luciferase assay was purchased from Promega (Madison, WI); B[a]P and B[a]PDE were from Eagle‐Picher Industries, Inc., Chemsyn Science Laboratories (Lenexa, KS); CDE and 5‐MCDE were synthesized as described [6,7]. B[a]P, B[a]PDE, CDE, or 5‐MCDE was dissolved in dimethylsulfoxide at 2‐mM stock concentration.…”

Section: Methodsmentioning

confidence: 99%

“…B[a]P, for instance, is metabolized by cytochrome P450 enzymes into its ultimate metabolite, benzo[a]pyrene‐7,8‐diol‐9,10‐epoxide (B[a]PDE), which binds to the N2 position of guanine and causes a G to T transversion mutation [4]. Exposure to PAHs is associated with an increased risk of cancers in various organ and tissues, including lung and skin [2,5–9]. For instance, B[a]P and its metabolite B[a]PDE have been shown to be complete carcinogens in various animal models [2,10–13].…”

Section: Introductionmentioning

confidence: 99%

“…For instance, B[a]P and its metabolite B[a]PDE have been shown to be complete carcinogens in various animal models [2,10–13]. 5‐MCDE has also been found to be strongly carcinogenic [2,6–8]. Most previous studies have focused on the mutagenicity of PAHs, revealing that the mutagenicity of PAHs is related to their structures and modifications in the bay region.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential effects of polycyclic aromatic hydrocarbons on transactivation of AP‐1 and NF‐κB in mouse epidermal cl41 cells

Li¹,

Chen²,

Ke³

et al. 2004

Molecular Carcinogenesis

View full text Add to dashboard Cite

Polycyclic aromatic hydrocarbons (PAHs) and their derivatives, such as benzo[a]pyrene (B[a]P), (+/-)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (B[a]PDE), and 5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE), are complete carcinogens. However, the tumor promotion effects of PAHs remain unclear. We therefore investigated the possible activation of activator protein-1 (AP-1) and nuclear factor-kappaB (NFkappaB) in mouse epidermal Cl41 cells after different PAHs treatments, including B[a]P, B[a]PDE, chrysene-1,2-diol-3,4-epoxid (CDE), and 5-MCDE. The results showed that B[a]PDE and 5-MCDE were able to activate AP-1 and NF-kappaB, whereas B[a]P showed only marginal effect on AP-1 activation, and B[a]P and CDE had no effect on NF-kappaB activation. Treatment with either B[a]PDE or 5-MCDE also resulted in mitogen-activated protein kinases (MAPKs) activation as well as inhibitory subunit kappa-B (IkappaBalpha) phosphorylation and degradation, whereas B[a]P and CDE had no effect. Pretreatment with PD98059, a specific inhibitor for extracellular signal-regulated protein kinases (ERKs) upstream kinase MEK1/2, or SB202190, a p38 kinase inhibitor, resulted in a dramatic inhibition of B[a]PDE-induced AP-1 transactivation. In addition, B[a]PDE-induced AP-1 activation was also inhibited by overexpressing a dominant negative mutant of JNK1 in the cells. All these suggest ERKs, c-jun N-terminal kinases (JNKs), and p38 kinase signal transduction pathways are required for AP-1 induction by B[a]PDE. Taken together, B[a]PDE and 5-MCDE are the active compounds of PAHs to initiate signaling pathways. Considering the important roles of AP-1 and NF-kappaB in tumor promotion, we speculated the activation of AP-1 and NF-kappaB by B[a]PDE and 5-MCDE may involve in their or their parent compounds' tumor promotion effects. This study may help in better understanding the tumor promotion effects of PAHs.

show abstract

Comparative tumorigenicity in newborn mice of chrysene- and 5-alkylchrysene-1,2-diol-3,4-epoxides

Cited by 10 publications

References 2 publications

PI-3K and Akt are mediators of AP-1 induction by 5-MCDE in mouse epidermal Cl41 cells

PI-3K and Akt are mediators of AP-1 induction by 5-MCDE in mouse epidermal Cl41 cells

Aryl hydrocarbon receptor signaling, toxicity, and gene expression responses to mono‐methylchrysenes

Differential effects of polycyclic aromatic hydrocarbons on transactivation of AP‐1 and NF‐κB in mouse epidermal cl41 cells

Contact Info

Product

Resources

About