Role of Zn(2+) in oxidative stress caused by endotoxin challenge.
The role of Zn(2+) in oxidative stress during endotoxemia was investigated. In rats fed a Zn(2+)-deficient diet (Zn(2+) concentration of less than 1.5 mg/kg) for 8 weeks, the Zn(2+) level in the serum was about 62% lower than that in rats fed a Zn(2+)-adequate diet (Zn(2+) concentration, 50 mg/kg). The Zn(2+) level in serum 18 h after administration of endotoxin (6 mg/kg, i.p.) to Zn(2+)-deficient diet rats was markedly lower than that of the endotoxin/Zn(2+)-adequate diet group. Lipid peroxide formation in the liver of Zn(2+)-deficient diet rats was markedly increased 18 h after endotoxin injection compared with that in the endotoxin/Zn(2+)-adequate diet group. Metallothionein in the liver of endotoxin/Zn(2+)-adequate diet rats was increased more than 17-fold by endotoxin administration, while a markedly lower level of metallothionein was observed in the endotoxin/Zn(2+)-deficient diet group. On the other hand, treatment with ZnSO(4) (100 microM) significantly increased endotoxin (1 microg/ml)-induced tumor necrosis factor-alpha (TNF-alpha) production in J774A.1 cells. Our results clearly demonstrated that treatment with ZnSO(4) significantly inhibited the endotoxin-induced increase in intracellular Ca(2+) level in J774A.1 cells. However, a cell membrane-permeable Zn(2+) chelator, N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN, 1 microM), did not affect the endotoxin-induced TNF-alpha production or Ca(2+) level in J774A.1 cells. In addition, we investigated whether Zn(2+) can suppress nitric oxide (NO) generation and cytotoxicity in endotoxin-treated cells. Treatment with ZnSO(4) (50 microM) significantly inhibited endotoxin-induced NO production in J774A.1 cells, but did not affect endotoxin-induced cytotoxicity. These findings suggest that zinc may play an important role, at least in part, in the oxidative stress during endotoxemia.
Sakaguchi
Shuhei
S
First Department of Hygienic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. shuhei@tohoku-pharm.ac.jp
Iizuka
Yukisumi
Y
Furusawa
Shinobu
S
Ishikawa
Masaaki
M
Satoh
Susumu
S
Takayanagi
Motoaki
M
D000818:Animals; D004032:Diet; D019446:Endotoxemia / Q000378:metabolism*; D008054:Lipid Peroxides / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015032:Zinc / Q000097:blood / Q000172:deficiency / Q000502:physiology
D008054:Lipid Peroxides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008668:Metallothionein; D015032:Zinc