Colchicine-induced elevation of tissue metallothionein contents is mediated by inflammation-independent serum factor.
Subcutaneous injection of colchicine caused dose-dependent and time-dependent induction of hepatic MT in mice. Other than colchicine, similar MT induction was observed in vincristine- or vinblastine-injected mice, but not in beta-lumicolchicine-injected mice. MT contents were also elevated in the kidney, spleen, lung and heart by colchicine injection. Isoforms of colchicine-induced MT in the liver were identified to be MT-I and II by immunoblot analysis. Unlike turpentine-induced MT synthesis, dexamethasone, an anti-inflammatory agent, could not block the MT-inducing activity of colchicine. Therefore, the MT-inducing activity of colchicine does not appear to be due to inflammation. Mouse serum, obtained at 4-24 h after colchicine treatment, stimulated MT induction in rat hepatoma H4IIEC3 cells. The MT-inducing activity in the serum from colchicine-treated mice was determined to be highest at 12 h after colchicine injection. The MT-inducing activity from sera of colchicine-treated mice was completely blocked by glucocorticoid antagonist, RU38486, similar to such activity in the serum from lipopolysaccharide-treated mice. The ability of sera to induce MT was abolished by heat treatment (56 degrees C, 30 min). The molecular weight of the MT-inducing factor estimated by gel filtration was approximately 20 000 Da. Thus, colchicine-induced stimulation of MT production is mediated by some humoral factor. The production of the MT-inducing factor was not blocked by dexamethasone. We conclude that the mediator is not an inflammatory cytokine or a glucocorticoid and suspect that the disruption of microtubule triggers production or release of such humoral mediator which stimulates MT induction.
Itoh
N
N
Faculty of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Kasamatsu
M
M
Onosaka
S
S
Muto
N
N
Tanaka
K
K
D000818:Animals; D001685:Biological Factors / Q000097:blood* / Q000494:pharmacology; D003078:Colchicine / Q000633:toxicity*; D006074:Gout Suppressants / Q000633:toxicity*; D007249:Inflammation / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015032:Zinc / Q000097:blood / Q000378:metabolism
D001685:Biological Factors; D006074:Gout Suppressants; D008668:Metallothionein; D015032:Zinc; D003078:Colchicine