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

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