Abstract
BackgroundAristolochic acid (AA) is the active component of herbal drugs derived from Aristolochia species that have been used for medicinal purposes since antiquity. AA, however, induced nephropathy and urothelial cancer in people and malignant tumors in the kidney and urinary tract of rodents. Although AA is bioactivated in both kidney and liver, it only induces tumors in kidney. To evaluate whether microarray analysis can be used for distinguishing the tissue-specific carcinogenicity of AA, we examined gene expression profiles in kidney and liver of rats treated with carcinogenic doses of AA.ResultsMicroarray analysis was performed using the Rat Genome Survey Microarray and data analysis was carried out within ArrayTrack software. Principal components analysis and hierarchical cluster analysis of the expression profiles showed that samples were grouped together according to the tissues and treatments. The gene expression profiles were significantly altered by AA treatment in both kidney and liver (p < 0.01; fold change > 1.5). Functional analysis with Ingenuity Pathways Analysis showed that there were many more significantly altered genes involved in cancer-related pathways in kidney than in liver. Also, analysis with Gene Ontology for Functional Analysis (GOFFA) software indicated that the biological processes related to defense response, apoptosis and immune response were significantly altered by AA exposure in kidney, but not in liver.ConclusionOur results suggest that microarray analysis is a useful tool for detecting AA exposure; that analysis of the gene expression profiles can define the differential responses to toxicity and carcinogenicity of AA from kidney and liver; and that significant alteration of genes associated with defense response, apoptosis and immune response in kidney, but not in liver, may be responsible for the tissue-specific toxicity and carcinogenicity of AA.
Highlights
Aristolochic acid (AA) is an active component of herbal drugs derived from Aristolochia species that have been used for medicinal purposes since antiquity
We found that the gene expression profiles were significantly altered by AA treatment in both kidney and liver, and many more significant genes involved in cancer-related pathways were found in kidney than in liver
In the original carcinogenesis study [11], atypical cells and hyperplasia were found in the kidney immediately after cessation of AA treatment while adenomas and adenocarcinomas were not observed until three months after the cessation of AA treatment
Summary
Aristolochic acid (AA) is the active component of herbal drugs derived from Aristolochia species that have been used for medicinal purposes since antiquity. The herbal drugs containing AA were used for treatment of snake bites, arthritis, gout, rheumatism and festering wounds, as well as used in obstetrics [1] This compound, is a nephrotoxin and carcinogen. The aristolochic acid nephropathy was initially observed in Belgium in 1991 and about half of the patients had renal replacement therapy [2,5,6]. Later, this disease was found in other European countries, and in Asia and the USA [1]. The International Agency for Research on Cancer (IARC) has classified the products containing AA as human carcinogens [14]
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