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The tumour suppressor<jats:italic>TP53<\/jats:italic>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<jats:italic>Trp53<\/jats:italic>(+<jats:italic>\/<\/jats:italic>+),<jats:italic>Trp53<\/jats:italic>(+<jats:italic>\/<\/jats:italic>\u2212) and<jats:italic>Trp53<\/jats:italic>(\u2212<jats:italic>\/<\/jats:italic>\u2212) mice with 3.5\u00a0mg\/kg body weight (bw) AAI daily for 2 or 6\u00a0days. Renal histopathology showed a gradient of intensity in proximal tubular injury from<jats:italic>Trp53<\/jats:italic>(+<jats:italic>\/<\/jats:italic>+) to<jats:italic>Trp53<\/jats:italic>(\u2212<jats:italic>\/<\/jats:italic>\u2212) mice, especially after 6\u00a0days. The observed renal injury was supported by nuclear magnetic resonance (NMR)-based metabonomic measurements, where a consistent<jats:italic>Trp53<\/jats:italic>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,<jats:italic>Trp53<\/jats:italic>genotype had no impact on AAI-DNA adduct levels, as measured by<jats:sup>32<\/jats:sup>P-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\u2013mass spectrometry (GC\u2013MS) on kidney tissues showed metabolic pathways affected by AAI treatment, but again<jats:italic>Trp53<\/jats:italic>status did not clearly impact on such metabolic profiles. We also cultured primary mouse embryonic fibroblasts (MEFs) derived from<jats:italic>Trp53<\/jats:italic>(+<jats:italic>\/<\/jats:italic>+),<jats:italic>Trp53<\/jats:italic>(+<jats:italic>\/<\/jats:italic>\u2212) and<jats:italic>Trp53<\/jats:italic>(\u2212<jats:italic>\/<\/jats:italic>\u2212) mice and exposed them to AAI in vitro (50\u00a0\u00b5M for up to 48\u00a0h). We found that<jats:italic>Trp53<\/jats:italic>genotype impacted on the expression of NAD(P)H:quinone oxidoreductase (Nqo1), a key enzyme involved in AAI bioactivation. Nqo1 induction was highest in<jats:italic>Trp53<\/jats:italic>(+<jats:italic>\/<\/jats:italic>+) MEFs and lowest in<jats:italic>Trp53<\/jats:italic>(\u2212<jats:italic>\/<\/jats:italic>\u2212) MEFs; and it correlated with AAI-DNA adduct formation, with lowest adduct levels being observed in AAI-exposed<jats:italic>Trp53<\/jats:italic>(\u2212<jats:italic>\/<\/jats:italic>\u2212) 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.<\/jats:p>","DOI":"10.1007\/s00204-019-02578-4","type":"journal-article","created":{"date-parts":[[2019,10,10]],"date-time":"2019-10-10T13:46:36Z","timestamp":1570715196000},"page":"3345-3366","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro"],"prefix":"10.1007","volume":"93","author":[{"given":"Mateja","family":"Sborchia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric G.","family":"De Prez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-H\u00e9l\u00e8ne","family":"Antoine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Bienfait","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radek","family":"Indra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Valbuena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00eblle L.","family":"Nortier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Stiborov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector C.","family":"Keun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4314-9318","authenticated-orcid":false,"given":"Volker M.","family":"Arlt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,10,10]]},"reference":[{"issue":"5","key":"2578_CR1","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1002\/ijc.10602","volume":"101","author":"VM Arlt","year":"2002","unstructured":"Arlt VM, Ferluga D, Stiborova M et al (2002a) Is aristolochic acid a risk factor for Balkan endemic nephropathy-associated urothelial cancer? 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