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We evaluated the effect of 19 hepatotoxicants and 20 antimetabolites on the expression of genes of the human nuclear receptor (NR) superfamily in human primary hepatocytes, utilizing NR superfamily-related data extracted from the toxicogenomics database Open TG-GATES. A considerable number of the drugs alone induced a significant fold change in the expression of a large number of NRs. The members of the NR superfamily that changed expression with more than 40% of the drugs consisted of 12 NRs common to both classes (COUP, FXR, HNF4, LRH1, LXR, PPAR PPAR, PXR, ROR, RXR, and TR4), 3 NRs specific to hepatotoxicants (GCNF1, RAR and TR), and 7 NRs specific to antimetabolites (ER GR, RAR REVERB RXRSHP, and VDR Nine of these were classified into cluster I involved in reproduction, development, and growth, whereas 13 were classified into cluster II, involved in nutrient uptake, metabolism, and excretion. These were also characterized by containing members of 6 out of 8 circadian-regulated subfamilies (ROR, Rev-erb, PPAR, FXR, TR, and TR2/TR4) including circadian oscillator genes Rev-erbs  and ROR and by containing 8 out of 9 NR subfamilies controlling the expression of genes for drug-metabolizing enzymes (CAR, FXR, GR, HNF4, LXR, PXR, PPAR, RAR, and VDR). The unsupervised hierarchical clustering of the NRs mobilized by drugs showed markedly different profiles between hepatotoxicants and antimetabolites. The results suggest that the profile of the expression response is determined by coordinated changes of drug-specific NRs and homeostasis-maintaining core NRs including circadian-regulated and circadian oscillator NRs and NRs controlling the expression of genes for drug-metabolizing enzymes. The hierarchial clustering of the hepatotoxicants and antimetabolites based on their effect on NRs showed that hepatotoxicants were classified into two subfamilies, one of which consisted exclusively of those inducing coagulopathy, while antimetabolites were divided into Chem-Bio Informatics Journal, Vol.16, pp.13-24 (2016) 14 4 subfamilies where functionally-related drugs were generally classified together but with some exceptions. The classification of drugs based on their effect on the NR superfamily would urge us to re-examine the profile of toxicological actions of the drugs.

Characteristic gene expression profile of nuclear receptor superfamily induced by hepatotoxic and antimetabolic drugs in human primary hepatocytes