On the bioactivation and genotoxic action of fluoranthene

Abstract

Fluoranthene (FA) was studied with respect to possible mechanisms of its high mutagenicity but low carcinogenicity, in comparison with the corresponding properties of benzo[a]pyrene (BaP), and with regard to the synergism of these two compounds shown by van Duuren and Goldschmidt (J Natl Cancer Inst 56, 1976, 1237). FA and BaP activated by S9 from Aroclor 1254 (PCB)-treated rats induce HPRT mutations in CHO cells with about equal effectiveness at the same exposure doses, which also lead to the same frequencies of repairable DNA adducts, enzyme-induced strand breaks being used as an indirect measure of adducts to DNA. FA was also shown to be an efficient inducer of SCE in human peripheral lymphocytes cocultivated with PCB-treated HepG2 cells or with liver cells from PCB-pretreated rats. For the induction of SCE, FA and BaP were shown to act additively. From metabolic studies with liver microsomes from C57Bl/6 mice it is concluded that, whereas BaP induces the metabolism of BaP to the mutagenic epoxide, neither BaP nor FA is able to induce the metabolism of FA. In mutation experiments with V79 cells (XEM2) constitutive for P450 IA1 activity, BaP 7,8-diol but not FA 2,3-diol provokes a high frequency of HPRT mutations. In cells constitutive for P450 IA2 enzymatic activity FA and BaP are but weakly mutagenic and practically nonmutagenic, respectively. Due to the additivity of the genotoxic effects of FA and BaP, induction of an error-prone condition by the latter compound seems to be excluded.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzo(a)pyrene modulates fluoranthene-induced cellular responses in HT-29 colon cells in a dual exposure system

“…Induction of CYP enzymes by BaP may have modulated the enzymatic metabolic activation of FLA thereby enhancing its carcinogenic potential. Our findings are in agreement with that of Vaca et al (1992) and Huderson et al (2010) who have shown that co-treatment with BaP induces the microsomal metabolism of FLA to precursors of reactive metabolites. Bio-tranformation of FLA by tumor cells may lead to production of intracellular metabolites (Buesen et al, 2002; Myers et al, 2011) whose production rate may have enhanced due to the action of BaP.…”

Comparative potency approach based on H2AX assay for estimating the genotoxicity of polycyclic aromatic hydrocarbons

“…These data are in agreement with other studies indicating that neither Fla nor Pyr was mutagenic or genotoxic γ H2AX fold induction 8 7 6 5 8 7 6 5 8 7 6 5 8 7 6 5 8 7 6 5 8 7 6 5 8 7 6 5 8 7 6 5 9 8 7 6 9 8 7 6 M 10 -X : (Vaca et al, 1992, Durant et al 1996Sjogren et al 1996). Although the carcinogenic potential of Fla is considered as equivocal (Wang and Busby, 1993;Wang et al, 1995;Stocker et al, 1996), both Pyr and Fla were classified as non-carcinogenic (IARC, 2010).…”

Cancer Risk Assessment, Indicators, and Guidelines for Polycyclic Aromatic Hydrocarbons in the Ambient Air

“…Fluoranthene, like B[a]P, is metabolized to mutagenic DEs and its mutagenic potency is close to that of B[a]P (Vaca et al 1992). The carcinogenic action of fluoranthene diolepoxide has been demonstrated experimentally .…”

“…The carcinogenic action of fluoranthene diolepoxide has been demonstrated experimentally . In carcinogenicity tests with high doses, however, B[a]P is considerably more effective than fluoranthene (Busby et al 1984), evidently because of the promoter action of B[a]P (Vaca et al 1992). Although fluoranthene is now considered a weak carcinogen (WHO/IPCS 1998), the observed cancer incidence and the numbers of tumors per animal are compatible with linear doseresponse relationships (Wang and Busby 1993).…”