Effect of several metallothionein inducers on oxidative stress defense mechanisms in rats.
One mechanism by which chemicals cause cellular injury is the formation of reactive oxygen species. In vitro studies have shown that metallothionein (MT), a small metal-binding, sulfhydryl-rich, readily inducible protein, can scavenge reactive oxygen species, especially hydroxyl radicals. Nevertheless, whether or not MT protects against oxidative stress in the intact animal is not known. Experimental induction of MT could help to clarify this question, however, it is unclear whether agents that induce MT also influence known antioxidant systems. Therefore, the present study was designed to determine whether the well-known MT inducers are specific for induction of MT or whether they might also influence other hepatic systems that protect against oxidative stress. Male rats were administered cadmium chloride (Cd; 30 mumol/kg, s.c.), zinc chloride (Zn; 1000 mumol/kg, s.c.), alpha-hederin (alpha-H, 30 mumol/kg, s.c.) or lipopolysaccharide (LPS; 1 mg/kg, s.c.) 24 h prior to measurement of antioxidant systems. Zn and alpha-H increased hepatic GSH concentration 20% and 55%, respectively. Cd significantly increased, whereas LPS reduced, the activities of selenium-dependent glutathione peroxidase and glutathione reductase. Glutathione S-transferases were not altered by any of the inducers. Cd also increased DT-diaphorase activity. Cd, Zn and alpha-H all decreased catalase activity 20-35%, while the activity of superoxide dismutase was unaffected by the inducers. The amount of total cytochrome P450 enzymes and cytochrome b5 were decreased by LPS, Cd and alpha-H, while Zn appeared to have no effect. The activities of P450 enzymes towards testosterone oxidation were also decreased by LPS, Cd and alpha-H. In conclusion, all four MT inducers examined affect systems known to protect cells against oxidative stress. Therefore, using these chemicals to determine the in vivo role of MT in protecting against oxidative stress poses difficulties.
Iszard
M B
MB
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City 66160-7417, USA.
Liu
J
J
Klaassen
C D
CD
D000704:Analysis of Variance; D000818:Animals; D002104:Cadmium / Q000008:administration & dosage / Q000633:toxicity; D019256:Cadmium Chloride; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D002374:Catalase / Q000378:metabolism; D002712:Chlorides / Q000008:administration & dosage / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015786:Cytochromes b5 / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D008058:Dihydrolipoamide Dehydrogenase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D009828:Oleanolic Acid / Q000031:analogs & derivatives*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012503:Saponins / Q000008:administration & dosage / Q000633:toxicity; D012643:Selenium / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D013739:Testosterone / Q000737:chemistry / Q000378:metabolism; D017967:Zinc Compounds / Q000008:administration & dosage / Q000633:toxicity
D002273:Carcinogens; D002712:Chlorides; D008070:Lipopolysaccharides; D012503:Saponins; D017967:Zinc Compounds; C010177:beta-hederin; D002104:Cadmium; D013739:Testosterone; D009828:Oleanolic Acid; C016837:zinc chloride; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D008668:Metallothionein; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D008058:Dihydrolipoamide Dehydrogenase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione; D012643:Selenium; D019256:Cadmium Chloride