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 beta-naphthoflavone (beta-NF), a CYP1A inducer, and andrographolide modified the expression of 45 genes (27 up-regulated and 18 down-regulated), although beta-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.
Chatuphonprasert
Waranya
W
Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Jarukamjorn
Kanokwan
K
Kondo
Sachiko
S
Nemoto
Nobuo
N
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D022781:Hepatocytes / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction / Q000187:drug effects; D019324:beta-Naphthoflavone / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D004791:Enzyme Inhibitors; C030419:andrographolide; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1