Effect of aminoguanidine on lipopolysaccharide-induced changes in rat liver transporters and transcription factors.
To determine the role of nitric oxide (NO) in rat liver transporter regulation, we investigated whether NO mediates lipopolysaccharide (LPS)-induced changes in transporters and their transcription factor expression using aminoguanidine (AG), an inhibitor of induced nitric oxide synthase (iNOS). We confirmed that LPS decreased mRNA levels for Ntcp, Oatp1, Oatp2, Oatp4, Oct1, Mrp2, Mdr1a and increased those for Mdr1b at 16 h after administration. AG attenuated these decreases for Ntcp, Oatp1 and Oatp4 (retinoid X receptor (RXR)alpha- and hepatocyte nuclear factor (HNF)4alpha-dependent genes) and increase for Mdr1b (nuclear factor (NF)-kappaB-dependent gene). Concomitantly, it suppressed LPS-induced NF-kappaB-dependent gene transcription, such as those for proinflammatory cytokines (cytokines; tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6) and iNOS, and also suppressed IL-1beta release from Kupffer cells (KCs) at post-translational levels, but had little effect on the LPS-induced decreases in RXRalpha and HNF4alpha transcriptional activities. These findings indicate that hepatocytes were stimulated directly by LPS, which lead to the activation of NF-kappaB and reduction of RXRalpha and HNF4alpha transcriptional activities as early responses, and indirectly by cytokines and NO released from KCs via activation of NF-kappaB by LPS as delayed responses. We conclude that AG, which suppresses LPS-induced NF-kappaB activation in both hepatocytes and KCs and then the release of cytokines and NO from KCs, attenuates LPS-induced changes of Ntcp, Oatp1, Oatp4 and Mdr1b transcription in hepatocytes. The roles of cytokines and NO could not be distinguished, however. Further in vitro study is needed to clarify the role of NO in transporter regulation.
Aoki
Kimiko
K
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. kimiko-aoki@kxd.biglobe.ne.jp
Nakajima
Miki
M
Hoshi
Yoshiyuki
Y
Saso
Naomi
N
Kato
Satoko
S
Sugiyama
Yuichi
Y
Sato
Hitoshi
H
D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004731:Endotoxins / Q000633:toxicity*; D006146:Guanidines / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D016207:Cytokines; D004731:Endotoxins; D006146:Guanidines; D026901:Membrane Transport Proteins; D014157:Transcription Factors; D009569:Nitric Oxide; C044101:endotoxin, Escherichia coli; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine