Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid

Endemic (Balkan) nephropathy is a chronic tubulointerstitial disease frequently accompanied by urothelial cell carcinomas of the upper urinary tract. This disorder has recently been linked to exposure to aristolochic acid, a powerful nephrotoxin and human carcinogen. Following metabolic activation,...

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Bibliographic Details
Published in:Kidney international 2012-03, Vol.81 (6), p.559-567
Main Authors: Jelaković, Bojan, Karanović, Sandra, Vuković-Lela, Ivana, Miller, Frederick, Edwards, Karen L., Nikolić, Jovan, Tomić, Karla, Slade, Neda, Brdar, Branko, Turesky, Robert J., Stipančić, Želimir, Dittrich, Damir, Grollman, Arthur P., Dickman, Kathleen G.
Format: Article
Language:English
Subjects:
Adducts
Adult
Aged
Aged, 80 and over
Aristolochia
Aristolochic acid
Aristolochic Acids - adverse effects
Aristolochic Acids - metabolism
Balkan Nephropathy - chemically induced
Balkan Nephropathy - diagnosis
Balkan Nephropathy - epidemiology
Balkan Nephropathy - genetics
Balkan Nephropathy - metabolism
Bioindicators
Biological and medical sciences
biomarkers
Biomarkers - analysis
Biotransformation
Bosnia and Herzegovina - epidemiology
Carcinogens
Carcinogens, Environmental - adverse effects
Carcinogens, Environmental - metabolism
Carcinoma
Carcinoma - chemically induced
Carcinoma - diagnosis
Carcinoma - epidemiology
Carcinoma - genetics
Carcinoma - metabolism
Case-Control Studies
Croatia - epidemiology
Diet
Diets
DNA
DNA adducts
DNA Adducts - analysis
DNA Mutational Analysis
endemic nephropathy
Environmental Exposure
Environmental Monitoring - methods
Epidemiological Monitoring
Female
Genetic Predisposition to Disease
genomics
Humans
Kidney
Kidney Cortex - chemistry
Kidney Cortex - drug effects
Kidney Cortex - pathology
Male
Mass Spectrometry
Mass spectroscopy
Medical sciences
Metabolic activation
Middle Aged
Molecular Epidemiology
Mutation
Nephrology. Urinary tract diseases
Nephropathy
nephrotoxicity
p53 protein
renal cortex
Residence Characteristics
Risk Assessment
Risk Factors
Serbia - epidemiology
Tumor Suppressor Protein p53 - genetics
Tumors
Tumors of the urinary system
upper urinary tract cancer
Urinary system involvement in other diseases. Miscellaneous
Urinary tract
Urinary tract. Prostate gland
Urine
Urologic Neoplasms - chemically induced
Urologic Neoplasms - diagnosis
Urologic Neoplasms - epidemiology
Urologic Neoplasms - genetics
Urologic Neoplasms - metabolism
urothelial carcinoma
urothelium
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Summary:Endemic (Balkan) nephropathy is a chronic tubulointerstitial disease frequently accompanied by urothelial cell carcinomas of the upper urinary tract. This disorder has recently been linked to exposure to aristolochic acid, a powerful nephrotoxin and human carcinogen. Following metabolic activation, aristolochic acid reacts with genomic DNA to form aristolactam-DNA adducts that generate a unique TP53 mutational spectrum in the urothelium. The aristolactam-DNA adducts are concentrated in the renal cortex, thus serving as biomarkers of internal exposure to aristolochic acid. Here, we present molecular epidemiologic evidence relating carcinomas of the upper urinary tract to dietary exposure to aristolochic acid. DNA was extracted from the renal cortex and urothelial tumor tissue of 67 patients that underwent nephroureterectomy for carcinomas of the upper urinary tract and resided in regions of known endemic nephropathy. Ten patients from nonendemic regions with carcinomas of the upper urinary tract served as controls. Aristolactam-DNA adducts were quantified by 32P-postlabeling, the adduct was confirmed by mass spectrometry, and TP53 mutations in tumor tissues were identified by chip sequencing. Adducts were present in 70% of the endemic cohort and in 94% of patients with specific A:T to T:A mutations in TP53. In contrast, neither aristolactam-DNA adducts nor specific mutations were detected in tissues of patients residing in nonendemic regions. Thus, in genetically susceptible individuals, dietary exposure to aristolochic acid is causally related to endemic nephropathy and carcinomas of the upper urinary tract.
ISSN:0085-2538
1523-1755
DOI:10.1038/ki.2011.371