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 (COUPβ, FXR, HNF4α, LRH1, LXRα, PPARα, PPARδ, PXR, RORα, RXRα, and TR4), 3 NRs specific to hepatotoxicants (GCNF1, RARβ, and TRβ), and 7 NRs specific to antimetabolites (ERα, GR, RARα, REVERBα, RXRβ, SHP, 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 α, β, and RORα and by containing 8 out of 9 NR subfamilies controlling the expression of genes for drug-metabolizing enzymes (CAR, FXR, GR, HNF4α, 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 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.
Allopurinol, the most traditional and widely used medication for hyperuricemia and gout, has been reported as a common cause of severe cutaneous adverse reactions. Allopurinol is rapidly and extensively metabolized to oxipurinol. At least six allopurinol-related impurities have been reported to be contained in allopurinol. It is of interest to identify the compound which is likely to be responsible to the adverse reactions. Since a strong association between allopurinol-induced adverse reactions and HLA-B*58:01 has been observed, binding of allopurinol-related compounds to HLA-B*58:01 must be important for the onset of the adverse reactions. In this study, using the three-dimensional structure of HLA-B*58:01 constructed by homology modeling, the binding modes and affinities between allopurinol-related compounds and HLA-B*58:01 were simulated by docking simulations. The results have indicated that the adverse reactions of allopurinol should be due very largely to oxipurinol. The results also suggested that the concentrations of several impurities currently approved by the United States Pharmacopeia should be strictly monitored not to exceed the limits because they may strongly bind to HLA-B*58:01 and possibly leading to more severe adverse reactions.
Carbamazepine (CBZ) is a widely used anticonvulsant and is one of the major causative drugs of cutaneous adverse drug reactions (cADRs), such as Stevens-Johnson syndrome and toxic epidermal necrolysis. For the East Asians and Europeans HLA-A*31:01 is associated with CBZ-induced cADRs. We have undertaken in silico docking simulations of CBZ and its metabolites at the peptide-binding groove of HLA-A*31:01 in order to identify the chemical species responsible for the CBZ-induced cADR.
A non-nucleoside reverse-transcriptase inhibitor nevirapine (NVP) used to treat HIV-1 infection can cause severe, life-threatening idiosyncratic drug toxicity (IDT). It is known that the IDT caused by NVP or its metabolites is associated with the HLA-B*14:02 haplotype. The molecular mechanism of the HLA-associated IDT, however, has not been disclosed. In this study, we have simulated the interaction modes between NVP-related compounds, HLA B*14:02, and a T-cell receptor in order to understand the molecular mechanism leading to the onset of IDT.
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