Synergistic increases of metabolism and oxidation–reduction genes on their expression after combined treatment with a CYP1A inducer and andrographolide

We previously reported that andrographolide greatly enhanced the expression of CYP1A1. Since andrographolide is a major constituent of Andrographis paniculata, which has been employed for centuries in Asia and Europe as a folk remedy, we further analyzed genes whose expression was modified by andrographolide using primary-cultured mouse hepatocytes in a microarray assay. With the threshold for modification set at 2-fold, andrographolide up-regulated 18 genes among 28,853 genes, most of them related to metabolism/oxidation/reduction. Meanwhile, 5 genes, related to protein binding or calcium ion binding, were down-regulated. A combination of β-naphthoflavone (β-NF), a CYP1A inducer, and andrographolide modified the expression of 45 genes (27 up-regulated and 18 down-regulated), although β-NF single treatment up-regulated 4 genes. The affected genes were again mostly related to metabolism and oxidation–reduction. Among P450 isoforms, andrographolide by itself induced CYP1A1, CYP2A4, CYP2B9, and CYP2B10 expression. Synergistic expression of CYP1A1 and CYP1B1 mRNA was confirmed by quantitative RT-PCR. These observations suggest that drug interaction and risk assessment with the use of andrographolide or A. paniculata should be elucidated.