The impact of p53 on aristolochic acid I-induced nephrotoxicity and DNA damage in vivo and in vitro.
Animals
Aristolochic Acids
/ metabolism
Cells, Cultured
Cytochrome P-450 CYP1A1
/ genetics
DNA Damage
Fibroblasts
/ drug effects
Gene Expression
/ drug effects
Kidney Function Tests
Kidney Tubules, Proximal
/ drug effects
Male
Mice, Inbred C57BL
Mice, Knockout
Mutagens
/ metabolism
NAD(P)H Dehydrogenase (Quinone)
/ genetics
Tumor Suppressor Protein p53
/ genetics
Aristolochic acid I
Carcinogen metabolism
DNA adducts
Mouse embryonic fibroblasts
Mouse models
Tumour suppressor p53
Journal
Archives of toxicology
ISSN: 1432-0738
Titre abrégé: Arch Toxicol
Pays: Germany
ID NLM: 0417615
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
16
07
2019
accepted:
17
09
2019
pubmed:
12
10
2019
medline:
28
8
2020
entrez:
12
10
2019
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31602497
doi: 10.1007/s00204-019-02578-4
pii: 10.1007/s00204-019-02578-4
pmc: PMC6823306
mid: EMS84632
doi:
Substances chimiques
Aristolochic Acids
0
Mutagens
0
Trp53 protein, mouse
0
Tumor Suppressor Protein p53
0
aristolochic acid I
94218WFP5T
Cyp1a1 protein, mouse
EC 1.14.14.1
Cytochrome P-450 CYP1A1
EC 1.14.14.1
NAD(P)H Dehydrogenase (Quinone)
EC 1.6.5.2
Nqo1 protein, mouse
EC 1.6.5.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3345-3366Subventions
Organisme : Cancer Research UK
ID : A14329
Pays : United Kingdom
Organisme : MRC-PHE Centre for Environment & Health
ID : PhD Studentship
Pays : International
Organisme : Cancer Research UK
ID : C313/A14329
Pays : United Kingdom
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