The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53(+/+), Trp53(+/–) and Trp53(−/−) mice

Krais, Annette M.; Speksnijder, Ewoud N.; Melis, Joost P.M.; Indra, Radek; Moserová, Michaela; Godschalk, Roger; Schooten, Frederik J. van; Seidel, Albrecht; Kopka, Klaus; Schmeiser, Heinz H.; Stiborová, Marie; Phillips, David H.; Luijten, Mirjam; Arlt, Volker M.

doi:10.1007/s00204-015-1531-8

Cited by 37 publications

(58 citation statements)

References 57 publications

(94 reference statements)

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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%

“…Similarly, WT and hSULT1A1/2 mice were injected i.p. with a single dose of 2 mg/kg body weight of 3-NBA according to treatment protocols used previously to study 3-NBA metabolism (Arlt et al 2005; Krais et al 2016a; Kucab et al 2016). 3-NBA was dissolved in tricaprylin at a concentration of 0.2 mg/mL.…”

Section: Methodsmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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“…p53 can be induced by multiple forms of cellular stress (e.g., DNA damage) and it functions at the crossroads of a network of signaling pathways that are crucial for regulating cell growth and apoptosis. Over recent years, a role for p53 in modulating carcinogen metabolism has emerged Simoes et al 2008;Krais et al 2016a;Krais et al 2016b;Wohak et al 2016;Willis et al 2018;Wohak et al 2018). Disruption of the normal p53 response by TP53 mutation leads to the development of tumors and various carcinogens have been associated with characteristic mutational signatures (Kucab et al 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Its response to DNA damage is to abrogate DNA synthesis or cell division and this has earned p53 the term "guardian of the genome." We have shown that DNA adduct formation by BaP was significantly impacted by p53 function both in vitro and in vivo and that the observed DNA damage correlates with CYP1A1 expression (Krais et al 2016a;Wohak et al 2016). In addition to the role of p53 in DNA damage response, new functions are still being discovered.…”

Section: Introductionmentioning

confidence: 99%

Impact of p53 function on the sulfotransferase‐mediated bioactivation of the alkylated polycyclic aromatic hydrocarbon 1‐hydroxymethylpyrene in vitro

Wohak

Monien

Phillips

et al. 2019

Environ and Mol Mutagen

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The tumor suppressor p53, encoded by TP53, is known as the “guardian of the genome.” Sulfotransferases (SULTs) are involved in the metabolism of alkylated polycyclic aromatic hydrocarbons such as 1‐hydroxymethylpyrene (1‐HMP), which is a known substrate for SULT1A1. To investigate the impact of TP53 on the metabolic activation of 1‐HMP, a panel of isogenic human colorectal HCT116 cells having TP53(+/+), TP53(+/−), or TP53(−/−) were treated with 10 μM 1‐HMP for 24 hr. 1‐HMP‐DNA adduct formation was determined by ultraperformance liquid chromatography‐tandem mass spectrometry analysis, which quantified two nucleoside adducts N2‐(1‐methylpyrenyl)‐2′‐deoxyguanosine and N6‐(1‐methylpyrenyl)‐2′‐deoxyadenosine. 1‐HMP treatment resulted in significantly (~40‐fold) higher DNA adduct levels in TP53(+/+) cells than in the other cell lines. Higher levels of 1‐HMP‐induced DNA adducts in TP53(+/+) cells correlated with higher basal expression of SULT1A1/3 in this cell line, but 1‐HMP treatment showed no effect on the expression of this protein. These results indicate that the cellular TP53 status is linked to the SULT1A1/3‐mediated bioactivation of 1‐HMP, thereby broadening the spectrum of p53's targets. Environ. Mol. Mutagen., 60:752–758, 2019. © 2019 Wiley Periodicals, Inc.

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Transcriptional profiling of the mouse hippocampus supports an NMDAR‐mediated neurotoxic mode of action for benzo[a]pyrene

Chepelev

Long

Bowers

et al. 2016

Environ and Mol Mutagen

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Benzo[a]pyrene (BaP) is a genotoxic carcinogen and a neurotoxicant. The neurotoxicity of BaP is proposed to arise from either genotoxicity leading to neuronal cell death, or perturbed expression of N‐methyl‐d‐aspartate receptor (NMDAR) subunits. To explore these hypotheses, we profiled hippocampal gene expression of adult male Muta™Mouse administered 0, 1, 35, or 70 mg BaP/kg bw per day by oral gavage for 3 days. Transcriptional profiles were examined by RNA‐sequencing (RNA‐seq), DNA microarrays, and real‐time quantitative reverse transcription polymerase chain reaction (RT‐PCR). BaP‐DNA adducts in the cerebellum were quantified by 32P‐post‐labeling to measure genotoxicity. RNA‐seq revealed altered expression of 0, 260, and 219 genes (P‐value < 0.05, fold‐change ≥ ± 1.5) following exposure to the low, medium, and high doses, respectively; 54 genes were confirmed by microarrays. Microarray and RT‐PCR analysis showed increased expression of NMDAR subunits Grina and Grin2a. In contrast, no effects on DNA‐damage response genes were observed despite comparable BaP‐DNA adduct levels in the cerebellum and in the lungs and livers of mice at similar BaP doses in previous studies. The results suggest that DNA‐damage response does not play a major role in BaP‐induced adult neurotoxicity. Meta‐analysis revealed that BaP‐induced transcriptional profiles are highly correlated with those from the hippocampus of transgenic mice exhibiting similar neurotoxicity outcomes to BaP‐exposed mice and rats (i.e., defects in learning and memory). Overall, we suggest that BaP‐induced neurotoxicity is more likely to be a consequence of NMDAR perturbation than genotoxicity, and identify other important genes potentially mediating this adverse outcome. Environ. Mol. Mutagen. 57:350–363, 2016. © 2016 Her Majesty the Queen in Right of Canada. Environmental and Molecular Mutagenesis © 2016 Environmental Mutagen Society.

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The impact of p53 on DNA damage and metabolic activation of the environmental carcinogen benzo[a]pyrene: effects in Trp53(+/+), Trp53(+/–) and Trp53(−/−) mice

Cited by 37 publications

References 57 publications

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

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

Impact of p53 function on the sulfotransferase‐mediated bioactivation of the alkylated polycyclic aromatic hydrocarbon 1‐hydroxymethylpyrene in vitro

Transcriptional profiling of the mouse hippocampus supports an NMDAR‐mediated neurotoxic mode of action for benzo[a]pyrene

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