PMC

A. A two-way hierarchical clustering dendrogram of DPGs that were differentially regulated by PCN or TCPOBOP in livers of wild-type mice. B. Cumulative expression of all differentially regulated DPGs in livers of vehicle-, PCN- and TCPOBOP-treated mice. C. Cumulative expression of all differentially regulated Phase-I drug-metabolizing enzymes in livers of vehicle-, PCN- and TCPOBOP-treated mice. D. Cumulative expression of all differentially regulated Phase-II drug-metabolizing enzymes in livers of vehicle-, PCN- and TCPOBOP-treated mice. E. Cumulative expression of all differentially regulated uptake transporters in livers of vehicle-, PCN- and TCPOBOP-treated mice. F. Cumulative expression of all differentially regulated efflux transporters in livers of vehicle-, PCN- and TCPOBOP-treated mice. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).

Regulation of Slc transporters by PCN and TCPOBOP in livers of wild-type mice. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).

Regulation of Abc transporters by PCN and TCPOBOP in livers of wild-type mice. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).

Regulation of the Phase-I Cyp3 (A) and Cyp4 (B) drug-metabolizing enzymes by PCN and TCPOBOP in livers of wild-type mice. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).

Regulation of nuclear receptors and transcription factors by PCN and TCPOBOP in livers of wild-type mice. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).

Regulation of the Phase-I Cyp1 (A) and Cyp2 (B) drug-metabolizing enzymes by PCN and TCPOBOP in livers of wild-type mice. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).

Regulation of Phase-II glutathione S-transferases (A), sulfotransferases (B), and UDP glucuronosyltransferases (C) by PCN and TCPOBOP in livers of wild-type mice. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).

Regulation of other Phase-I drug-metabolizing enzymes by PCN and TCPOBOP in livers of wild-type mice: (A) carboxyesterases; (B) dehydrogenases and reductases. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05)

Regulation of other Phase-I drug-metabolizing enzymes by PCN and TCPOBOP in livers of wild-type mice: (A) alcohol and aldehyde metabolizing enzymes; (B) dehydrogenases and reductases. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).

Regulation of genes involved in oxidative stress and redox-cycling (A), as well as other Phase-I genes (B) by PCN and TCPOBOP in livers of wild-type mice. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05)

A. A diagram illustrating the experimental design and dosing regimen of mice. B. A venn diagram demonstrating the number of differentially regulated genes in livers of wild-type mice treated with PCN or TCPOBOP as compared to vehicle-treated group. Differential expression was determined using Cuffdiff with FDR<0.05 as described in MATERIALS AND METHODS. C. Top canonical pathways of the liver genes that are differentially regulated by both PCN and TCPOBOP (C-1), by PCN only (C-2), and by TCPOBOP only (C-3). Data were analyzed using Ingenuity Pathway Analysis as described in MATERIALS AND METHODS.

Regulation of the Cyps involved in bile acid and steroid synthesis and retinoic acid metabolism (A) and Cyp-related enzymes (B) by PCN and TCPOBOP in livers of wild-type mice. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).

Regulation of genes involved in histone methylation and demethylation (A), histone acetylation (B), and other histone modifications (phosphorylation, ubiquitination, chromatin remodeling, and histone expression) (C), by PCN and TCPOBOP in livers of wild-type mice. Only the differentially expressed genes in either PCN- or TCPOBOP-treated groups are presented. Genes in the same family are graphed together to quantitatively compare the mRNA abundance, and are graphed individually to better visualize the mRNA fold-changes by PCN or TCPOBOP of all genes. Asterisks represent statistically significant differences as compared to corn oil-treated group (FDR-adjusted p value <0.05).