Exposure to benzo[a]pyrene of Hepatic Cytochrome P450 Reductase Null (HRN) and P450 Reductase Conditional Null (RCN) mice: Detection of benzo[a]pyrene diol epoxide-DNA adducts by immunohistochemistry and 32P-postlabelling

Arlt, Volker M.; Poirier, Miriam C.; Sykes, Sarah E.; John, Kaarthik; Moserová, Michaela; Stiborová, Marie; Wolf, C. Roland; Henderson, Colin J.; Phillips, David H.

doi:10.1016/j.toxlet.2012.06.016

Cited by 31 publications

(61 citation statements)

References 34 publications

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“…However, previous studies ( Arlt et al. , 2008 , 2012 ; Nebert et al. , 2013 ) have revealed a paradox, whereby CYP enzymes (particularly CYP1A1) appear to be more important for detoxification of BaP in vivo , despite being involved in its metabolic activation in vitro .…”

Section: Discussionmentioning

confidence: 94%

Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene

et al. 2015

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Pulmonary inflammation can contribute to the development of lung cancer in humans. We investigated whether pulmonary inflammation alters the genotoxicity of polycyclic aromatic hydrocarbons (PAHs) in the lungs of mice and what mechanisms are involved. To model nonallergic acute inflammation, mice were exposed intranasally to lipopolysaccharide (LPS; 20 µg/mouse) and then instilled intratracheally with benzo[a]pyrene (BaP; 0.5 mg/mouse). BaP-DNA adduct levels, measured by 32P-postlabeling analysis, were approximately 3-fold higher in the lungs of LPS/BaP-treated mice than in mice treated with BaP alone. Pulmonary Cyp1a1 enzyme activity was decreased in LPS/BaP-treated mice relative to BaP-treated mice suggesting that pulmonary inflammation impacted on BaP-induced Cyp1a1 activity in the lung. Our results showed that Cyp1a1 appears to be important for BaP detoxification in vivo and that the decrease of pulmonary Cyp1a1 activity in LPS/BaP-treated mice results in a decrease of pulmonary BaP detoxification, thereby enhancing BaP genotoxicity (ie, DNA adduct formation) in the lung. Because less BaP was detoxified by Cyp1a1 in the lungs of LPS/BaP-treated mice, more BaP circulated via the blood to extrapulmonary tissues relative to mice treated with BaP only. Indeed, we observed higher BaP-DNA adduct levels in livers of LPS/BaP-treated mice compared with BaP-treated mice. Our results indicate that pulmonary inflammation could be a critical determinant in the induction of genotoxicity in the lung by PAHs like BaP. Cyp1a1 appears to be involved in both BaP bioactivation and detoxification although the contribution of other enzymes to BaP-DNA adduct formation in lung and liver under inflammatory conditions remains to be explored.

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Section: Discussionmentioning

confidence: 94%

Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene

et al. 2015

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“…They also consider factors such as induction and/or inhibition of XMEs, as well as the presence of a variety of phase I and II enzymes, as critical determinants for the formation of reactive AA metabolites in vivo capable of forming DNA adducts. Several studies have shown that XMEs can behave differently in vitro and in vivo (Arlt et al 2008, 2012; Krais et al 2016a; Wohak et al 2016). For example, some studies have revealed a paradox whereby CYP enzymes (particularly CYP1A1) appear to be more important for detoxification of benzo[ a ]pyrene in vivo, despite being involved in its metabolic activation in vitro (Arlt et al 2008; Nebert et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone

et al. 2016

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Exposure to aristolochic acid (AA) causes aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN). Conflicting results have been found for the role of human sulfotransferase 1A1 (SULT1A1) contributing to the metabolic activation of aristolochic acid I (AAI) in vitro. We evaluated the role of human SULT1A1 in AA bioactivation in vivo after treatment of transgenic mice carrying a functional human SULT1A1-SULT1A2 gene cluster (i.e. hSULT1A1/2 mice) and Sult1a1(−/−) mice with AAI and aristolochic acid II (AAII). Both compounds formed characteristic DNA adducts in the intact mouse and in cytosolic incubations in vitro. However, we did not find differences in AAI-/AAII-DNA adduct levels between hSULT1A1/2 and wild-type (WT) mice in all tissues analysed including kidney and liver despite strong enhancement of sulfotransferase activity in both kidney and liver of hSULT1A1/2 mice relative to WT, kidney and liver being major organs involved in AA metabolism. In contrast, DNA adduct formation was strongly increased in hSULT1A1/2 mice compared to WT after treatment with 3-nitrobenzanthrone (3-NBA), another carcinogenic aromatic nitro compound where human SULT1A1/2 is known to contribute to genotoxicity. We found no differences in AAI-/AAII-DNA adduct formation in Sult1a1(−/−) and WT mice in vivo. Using renal and hepatic cytosolic fractions of hSULT1A1/2, Sult1a1(−/−) and WT mice, we investigated AAI-DNA adduct formation in vitro but failed to find a contribution of human SULT1A1/2 or murine Sult1a1 to AAI bioactivation. Our results indicate that sulfo-conjugation catalysed by human SULT1A1 does not play a role in the activation pathways of AAI and AAII in vivo, but is important in 3-NBA bioactivation.

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“…Female Xpa-WT and Xpa-Null Hupki mice (∼3 months old) were treated with BaP as indicated below and sacrificed either 24 h or 5 days after the last administration following treatment regimens published previously [28,32] . Several organs (liver, lung, small intestine, spleen, colon and kidney) were removed, snap frozen in liquid N 2 , and stored at −80 °C until analysis.…”

Section: Methodsmentioning

confidence: 99%

TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts

Kucab

Steeg

Luijten

et al. 2015

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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HighlightsWe have generated Xpa-Null Hupki (Human TP53 knock-in) mouse embryo fibroblasts (HUFs).Xpa-Null HUFs can be used to study the impact of nucleotide excision repair on TP53 mutagenesis.Xpa-Null HUFs exhibit increased sensitivity to benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE).BPDE-induced TP53 mutagenesis is enhanced on the transcribed strand in Xpa-Null HUFs.Several TP53 codons mutated by BPDE in HUFs are mutational hotspots in smokers’ lung cancer.

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Exposure to benzo[a]pyrene of Hepatic Cytochrome P450 Reductase Null (HRN) and P450 Reductase Conditional Null (RCN) mice: Detection of benzo[a]pyrene diol epoxide-DNA adducts by immunohistochemistry and 32P-postlabelling

Cited by 31 publications

References 34 publications

Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene

Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene

Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone

TP53 mutations induced by BPDE in Xpa-WT and Xpa-Null human TP53 knock-in (Hupki) mouse embryo fibroblasts

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