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

Arlt, Volker M.; Krais, Annette M.; Godschalk, Roger; Riffo‐Vasquez, Yanira; Mrizova, Iveta; Roufosse, Candice; Corbin, Charmaine; Shi, Quan; Frei, Eva; Stiborová, Marie; Schooten, Frederik‐Jan van; Phillips, David H.; Spina, Domenico

doi:10.1093/toxsci/kfv086

Cited by 70 publications

(54 citation statements)

References 58 publications

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“…For example, the reactive form of BaP (i.e., benzo(a)pyrenediol-epoxide; BPDE) has been identified in serum following an oral exposure to BaP [Ginsberg and Atherholt, 1989]; however, due to the highly reactive nature of these metabolites, it is more likely that the production of DNAreactive metabolites occurs in situ in each tissue. Indeed, it has previously been demonstrated in several mouse models that the tissues examined here have constitutive or inducible levels of CYP1A1, 1A2, and/or 1B1, all of which are known to convert PAHs to DNA-reactive metabolites [Choudhary et al, 2003;Nebert et al, 2004;Uno et al, 2008;Renaud et al, 2011;Nebert et al, 2013;Arlt et al, 2015]. Moreover, our lab group has previously demonstrated induction of CYP1A1 and 1B1 in Muta-TM Mouse lung and liver following an identical oral exposure regime to several individual PAHs [Labib et al, 2015].…”

Section: Discussionmentioning

confidence: 67%

Oral exposure to commercially available coal tar‐based pavement sealcoat induces murine genetic damage and mutations

Long

Watson

Arlt

et al. 2016

Environ and Mol Mutagen

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Coal tar (CT) is a thick black liquid produced as a by‐product of coal carbonization to produce coke or manufactured gas. It is comprised a complex mixture of polycyclic aromatic compounds, including a wide range of polycyclic aromatic hydrocarbons (PAHs), many of which are genotoxic and carcinogenic. CT is used in some pavement sealants (also known as sealcoat), which are applied to pavement in order to seal and beautify the surface. Human exposure is known to occur not only during application, but also as a result of the weathering process, as elevated levels of PAHs have been found in settled house dust in residences adjacent to CT‐sealed surfaces. In this study we examined the genotoxicity of an extract of a commercially available CT‐based sealcoat in the transgenic Muta™Mouse model. Mice were orally exposed to 3 doses of sealcoat extract daily for 28 days. We evaluated genotoxicity by examining: (1) stable DNA adducts and (2) lacZ mutations in bone marrow, liver, lung, small intestine, and glandular stomach, as well as (3) micronucleated red blood cells. Significant increases were seen for each endpoint and in all tissues. The potency of the response differed across tissues, with the highest frequency of adducts occurring in liver and lung, and the highest frequency of mutations occurring in small intestine. The results of this study are the first demonstration of mammalian genotoxicity following exposure to CT‐containing pavement sealcoat. This work provides in vivo evidence to support the contention that there may be adverse health effects in mammals, and potentially in humans, from exposure to coal tar. Environ. Mol. Mutagen. 57:535–545, 2016. © 2016 Her Majesty the Queen in Right of Canada

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Section: Discussionmentioning

confidence: 67%

Oral exposure to commercially available coal tar‐based pavement sealcoat induces murine genetic damage and mutations

Long

Watson

Arlt

et al. 2016

Environ and Mol Mutagen

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“…Based on amounts of BaP-7,8-dihydrodiol, BaP-3-ol, and BaP-9-ol formed by individual human CYP enzymes, and expression levels of CYPs in human liver, we determined the contributions of CYPs to their formation in this human organ. However, it should be noted that actual hepatic concentrations are also influenced by the phase II enzymes [Shi et al, 2015] that were not evaluated in the present study. In human liver CYP1A1 and CYP2C19 are Environmental and Molecular Mutagenesis.…”

Section: Discussionmentioning

confidence: 84%

“…1). The major product of the reaction of BPDE with DNA in vitro and in vivo is the adduct 10-(deoxyguanosin-N 2 -yl) 27,8,9-trihydroxy-7,8,9,10tetrahydrobenzo[a]pyrene (dG-N 2 -BPDE) [Bauer et al, 1995;Arlt et al, 2008Arlt et al, , 2015Kucab et al, 2015]. However, BaP is also oxidized to other metabolites such as other dihydrodiols, BaP-diones and hydroxylated metabolites [Bauer et al, 1995;Kim et al, 1998;Baird et al, 2005;Jiang et al, 2007].…”

Section: Introductionmentioning

confidence: 99%

The impact of individual cytochrome P450 enzymes on oxidative metabolism of benzo[a]pyrene in human livers

Šulc

Indra

Moserová

et al. 2016

Environ and Mol Mutagen

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Benzo[a]pyrene (BaP) is a human carcinogen that covalently binds to DNA after metabolic activation by cytochrome P450 (CYP) enzymes. In this study human recombinant CYPs (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, and 3A5) were expressed in Supersomes™ together with their reductases, NADPH:CYP oxidoreductase, epoxide hydrolase and cytochrome b5, to investigate BaP metabolism. Human CYPs produced up to eight BaP metabolites. Among these, BaP‐7,8‐dihydrodiol and BaP‐9‐ol, which are intermediates in BaP‐derived DNA adduct formation, were mainly formed by CYP1A1 and 1B1, and to a lesser extent by CYP2C19 and 3A4. BaP‐3‐ol, a metabolite that is a ‘detoxified’ product of BaP, was formed by most human CYPs tested, although CYP1A1 and 1B1 produced it the most efficiently. Based on the amounts of the individual BaP metabolites formed by these CYPs and their expression levels in human liver, we determined their contributions to BaP metabolite formation in this organ. Our results indicate that hepatic CYP1A1 and CYP2C19 are most important in the activation of BaP to BaP‐7,8‐dihydrodiol, whereas CYP2C19, 3A4, and 1A1 are the major enzymes contributing to the formation of BaP‐9‐ol. BaP‐3‐ol is predominantly formed by hepatic CYP3A4, while CYP1A1 and 2C19 are less active. Environ. Mol. Mutagen. 57:229–235, 2016. © 2016 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.

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“…Hepatic and renal cytosols were isolated as described (Arlt et al 2008, 2015b; Krais et al 2016a, b). Because treating the mice with AAI or AAII might influence levels and activities of xenobiotic-metabolising enzymes (XMEs), cytosols were isolated from organs of both control (vehicle-treated) and AAI-AAII-treated mice (see above).…”

Section: Methodsmentioning

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

Cited by 70 publications

References 58 publications

Oral exposure to commercially available coal tar‐based pavement sealcoat induces murine genetic damage and mutations

Oral exposure to commercially available coal tar‐based pavement sealcoat induces murine genetic damage and mutations

The impact of individual cytochrome P450 enzymes on oxidative metabolism of benzo[a]pyrene in human livers

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

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