Possible involvement of interleukin-6 (IL-6) in down-regulation of hepatic breast cancer resistance protein (Bcrp/ABCG2) in endotoxemic mice

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The effect of endotoxin on the function and expression of hepatic breast cancer resistance protein (Bcrp/ABCG2), and ATP binding cassette (ABC) transporting protein, was investigated in mice. We measured the hepatobiliary excretion of mitoxantrone, which is a substrate for Bcrp, in mice at different times after intraperitoneal injection of endotoxin (10 mg/kg). The effects of endotoxin-overproduced cytokines, interleukin-6 (IL-6) and IL-1 β, on the function and expression of hepatic Bcrp were also examined. In vivo clearance experiments showed that the biliary clearance (CL_<BILE>) of mitoxantrone was significantly decreased not 6 h but 24 h after endotoxininjection. Both Western blot and immunofluorescence analyses revealed that the protein levels of hepatic Bcrp were decreased 24 h after injection of enddotoxin, which were consistent with the results from in vivo clearance experiments. Endotoxin significantly induced the overproduction of the cytokines IL-6 and IL-1 β. Pretreatment with IL-6 (2,500, 10,000 and 50,000 U/mouse) significantly decreased the CL_<BILE> of mitoxantrone. Western blot and immunofluorescence analyses also revealed that IL-6 at the highest dose significantly down-regulated hepatic Bcrp, which was in line with in vivo clearance experiments. However, IL-1 β at the same doses as IL-6 had no effect on the hepatobiliary excretion of mitoxantrone and expression of hepatic bcrp. These findings suggest that endotoxin reduces Bcrp-mediated hepatobiliary excretion of mitoxantrone by decreasing the expression of hepatic Bcrp, which is lifely due to increased IL-6 levels.
愛知文教女子短期大学の論文

Possible involvement of interleukin-6 (IL-6) in down-regulation of hepatic breast cancer resistance protein (Bcrp/ABCG2) in endotoxemic mice

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