Gene expression profiles distinguish the carcinogenic effects of aristolochic acid in target (kidney) and non-target (liver) tissues in rats.
BACKGROUND
Aristolochic 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.


RESULTS
Microarray 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.


CONCLUSIONS
Our 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.
Chen
Tao
T
Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, US FDA, Jefferson, AR 72079, USA. tao.chen@fda.hhs.gov
Guo
Lei
L
Zhang
Lu
L
Shi
Leming
L
Fang
Hong
H
Sun
Yongming
Y
Fuscoe
James C
JC
Mei
Nan
N
D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D001699:Biometry; D002273:Carcinogens / Q000633:toxicity*; D016000:Cluster Analysis; D019295:Computational Biology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D011916:Rats, Inbred F344
D034341:Aristolochic Acids; D002273:Carcinogens; C000228:aristolochic acid I