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

Wohak, Laura E.; Monien, Bernhard H.; Phillips, David H.; Arlt, Volker M.

doi:10.1002/em.22299

Cited by 6 publications

(3 citation statements)

References 33 publications

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“…Cells with elevated SULT1A1 level (HepG2 and V79 CS) display higher DNA adduct levels as compared to cells with moderate SULT1A1 expression (HCT116-p53 +/+ ). An interesting observation are the different SULT1A1 levels found in HCT116-p53 +/+ and HCT116-p53 −/− cells, which is in line with a previous study [ 24 ]. In parental V79 cells with very low endogenous SULT1A1 expression, DNA adduct formation was strongly reduced.…”

Section: Discussionsupporting

confidence: 92%

p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol

et al. 2022

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Liver cancer is one of the most frequent tumor entities worldwide, which is causally linked to viral infection, fatty liver disease, life-style factors and food-borne carcinogens, particularly aflatoxins. Moreover, genotoxic plant toxins including phenylpropenes are suspected human liver carcinogens. The phenylpropene methyleugenol (ME) is a constituent of essential oils in many plants and occurs in herbal medicines, food, and cosmetics. Following its uptake, ME undergoes Cytochrome P450 (CYP) and sulfotransferase 1A1 (SULT1A1)-dependent metabolic activation, giving rise to DNA damage. However, little is known about the cellular response to the induced DNA adducts. Here, we made use of different SULT1A1-proficient cell models including primary hepatocytes that were treated with 1′-hydroxymethyleugenol (OH-ME) as main phase I metabolite. Firstly, mass spectrometry showed a concentration-dependent formation of N2-MIE-dG as major DNA adduct, strongly correlating with SULT1A1 expression as attested in cells with and without human SULT1A1. ME-derived DNA damage activated mainly the ATR-mediated DNA damage response as shown by phosphorylation of CHK1 and histone 2AX, followed by p53 accumulation and CHK2 phosphorylation. Consistent with these findings, the DNA adducts decreased replication speed and caused replication fork stalling. OH-ME treatment reduced viability particularly in cell lines with wild-type p53 and triggered apoptotic cell death, which was rescued by pan-caspase-inhibition. Further experiments demonstrated mitochondrial apoptosis as major cell death pathway. ME-derived DNA damage caused upregulation of the p53-responsive genes NOXA and PUMA, Bax activation, and cytochrome c release followed by caspase-9 and caspase-3 cleavage. We finally demonstrated the crucial role of p53 for OH-ME triggered cell death as evidenced by reduced pro-apoptotic gene expression, strongly attenuated Bax activation and cell death inhibition upon genetic knockdown or pharmacological inhibition of p53. Taken together, our study demonstrates for the first time that ME-derived DNA damage causes replication stress and triggers mitochondrial apoptosis via the p53-Bax pathway.

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Section: Discussionsupporting

confidence: 92%

p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol

et al. 2022

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“…Given the clear link between AAI exposure and p53, it is important to study the role of this gene in AAI tumourigenesis. Previous studies have demonstrated that p53 can impact on carcinogen metabolism (Krais et al 2016a, b; Willis et al 2018; Wohak et al 2016, 2018, 2019). It has also been shown that p53 impacts on the bioactivation of AAI in vitro (Simoes et al 2008), a phenomenon which requires further investigations to better understand host factors modulating AAI-induced carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

et al. 2019

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Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. The tumour suppressor TP53 is a critical gene in carcinogenesis and frequently mutated in AA-induced urothelial tumours. We investigated the impact of p53 on AAI-induced nephrotoxicity and DNA damage in vivo by treating Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice with 3.5 mg/kg body weight (bw) AAI daily for 2 or 6 days. Renal histopathology showed a gradient of intensity in proximal tubular injury from Trp53(+/+) to Trp53(−/−) mice, especially after 6 days. The observed renal injury was supported by nuclear magnetic resonance (NMR)-based metabonomic measurements, where a consistent Trp53 genotype-dependent trend was observed for urinary metabolites that indicate aminoaciduria (i.e. alanine), lactic aciduria (i.e. lactate) and glycosuria (i.e. glucose). However, Trp53 genotype had no impact on AAI-DNA adduct levels, as measured by 32P-postlabelling, in either target (kidney and bladder) or non-target (liver) tissues, indicating that the underlying mechanisms of p53-related AAI-induced nephrotoxicity cannot be explained by differences in AAI genotoxicity. Performing gas chromatography–mass spectrometry (GC–MS) on kidney tissues showed metabolic pathways affected by AAI treatment, but again Trp53 status did not clearly impact on such metabolic profiles. We also cultured primary mouse embryonic fibroblasts (MEFs) derived from Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice and exposed them to AAI in vitro (50 μM for up to 48 h). We found that Trp53 genotype impacted on the expression of NAD(P)H:quinone oxidoreductase (Nqo1), a key enzyme involved in AAI bioactivation. Nqo1 induction was highest in Trp53(+/+) MEFs and lowest in Trp53(−/−) MEFs; and it correlated with AAI-DNA adduct formation, with lowest adduct levels being observed in AAI-exposed Trp53(−/−) MEFs. Overall, our results clearly demonstrate that p53 status impacts on AAI-induced renal injury, but the underlying mechanism(s) involved remain to be further explored. Despite the impact of p53 on AAI bioactivation and DNA damage in vitro, such effects were not observed in vivo.

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“…) of dG (Moon & Moschel, ; Moschel, Hudgins, & Dipple, ; Peterson, ). PAHs such as halomethyl‐ or sulfoxymethyl‐anthracenes as well as 1‐methylpyrene contribute to N 2 ‐(9‐anthracenylmethyl)‐dG ( N 2 ‐Anth‐dG) and N 2 ‐(1‐pyrenylmethyl)‐dG ( N 2 ‐Pyre‐dG) adduct formation (Bendadani et al., ; Bendadani, Meinl, Monien, Dobbernack, & Glatt, ; Casale & McLaughlin, ; Wohak, Monien, Phillips, & Arlt, ). Lucidin, a metabolite from madder root, is responsible for forming N 2 ‐Luc‐dG DNA adducts (Ishii et al., ; Ishii et al., ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of N²‐Aryl‐2′‐Deoxyguanosine Modified Phosphoramidites and Oligonucleotides

Ghodke

Pradeepkumar

2019

CP Nucleic Acid Chemistry

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The N2‐position of 2′‐deoxyguanosine (N2‐position in dG) is well known for forming carcinogenic minor groove DNA adducts, which originate from environmental pollutants, chemicals, and tobacco smoke. The N2‐dG DNA adducts have strong implications on biological processes such as DNA replication and repair and may, therefore, result in genomic instability by generating mutations or even cell death. It is crucial to know the role of DNA polymerases when they encounter the N2‐dG damaged site in DNA. To get detailed insights on the in vitro DNA damage tolerance or bypass mechanism, there is a need to synthetically access N2‐dG damaged DNAs. This article describes a detailed protocol of the synthesis of N2‐aryl‐dG modified nucleotides using the Buchwald‐Hartwig reaction as a main step and incorporation of the modified nucleotides into DNA. In Basic Protocol 1, we focused on the synthesis of five different N2‐dG modified phosphoramidites with varying bulkiness (benzyl to pyrenyl). Basic Protocol 2 describes the details of synthesizing N2‐dG modified oligonucleotides employing the standard solid phase synthesis protocol. This strategy provides robust synthetic access to various modifications at the N2‐position of dG; the modified dGs serve as good substrates to study translesion synthesis and repair pathways. Overall data presented in this article are based on earlier published reports. © 2019 by John Wiley & Sons, Inc.

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

Cited by 6 publications

References 33 publications

p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol

p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol

The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

Synthesis of N²‐Aryl‐2′‐Deoxyguanosine Modified Phosphoramidites and Oligonucleotides

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

Cited by 6 publications

References 33 publications

p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol

p53 triggers mitochondrial apoptosis following DNA damage-dependent replication stress by the hepatotoxin methyleugenol

The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro

Synthesis of N2‐Aryl‐2′‐Deoxyguanosine Modified Phosphoramidites and Oligonucleotides

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Synthesis of N²‐Aryl‐2′‐Deoxyguanosine Modified Phosphoramidites and Oligonucleotides