title: Cyclosporin A causes a hypermetabolic state and hypoxia in the liver: prevention by dietary glycine.
abstract: Acute cyclosporin A (CsA) treatment inhibits mitochondrial respiration, yet effects of chronic treatment remain unclear. Accordingly, the effects of chronic CsA on oxygen metabolism in perfused rat liver and isolated mitochondria were investigated. Basal rates of oxygen uptake of around 120 micromol/g/h in isolated perfused livers from vehicle-treated controls were elevated about 1.6-fold by chronic CsA treatment. In the presence of ammonium chloride, a substrate for urea synthesis, oxygen uptake was about 150 micromol/g/h and was increased about 1.7-fold by CsA, indicating that chronic CsA treatment causes a robust hypermetabolic state in the liver. In isolated mitochondria, state 3 rates of oxygen uptake were increased about 1.6-fold by chronic CsA treatment. Since significant increases in oxygen consumption could cause hypoxia, the hypoxia marker pimonidazole was given. Pimonidazole binding in the liver was increased about 3-fold by chronic CsA. Moreover, intracellular calcium in Kupffer cells isolated from vehicle-treated rats was not altered by CsA addition; however, in cells isolated from chronic CsA-treated rats, CsA increased intracellular calcium about 15-fold and prostaglandin E(2) (PGE(2)) production 3.5-fold. Importantly, dietary glycine (5%) largely blocked chronic CsA-induced activation of Kupffer cells, blunted production of PGE(2), prevented the hypermetabolic state, and minimized tissue hypoxia. Taken together, it is concluded that chronic CsA treatment causes a hypermetabolic state leading to hypoxia and injury to the liver. It is hypothesized that CsA activates Kupffer cells and increases production of PGE(2), which alters mitochondria leading to a hypermetabolic state. Glycine inhibits activation of Kupffer cells thus preventing liver injury.
authors.affiliation: Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7365, USA. zzhong@med.unc.edu
authors.forename: Z
authors.initials: Z
authors.lastname: Zhong
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Yamashina
authors.forename: M
authors.initials: M
authors.lastname: von Frankenberg
authors.forename: N
authors.initials: N
authors.lastname: Enomoto
authors.forename: K
authors.initials: K
authors.lastname: Ikejima
authors.forename: M
authors.initials: M
authors.lastname: Kolinsky
authors.forename: J A
authors.initials: JA
authors.lastname: Raleigh
authors.forename: R G
authors.initials: RG
authors.lastname: Thurman
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D016572:Cyclosporine / Q000633:toxicity*; D019587:Dietary Supplements; D015232:Dinoprostone / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D005998:Glycine / Q000627:therapeutic use*; D000860:Hypoxia / Q000139:chemically induced / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000633:toxicity; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D014508:Urea; D015232:Dinoprostone; D002118:Calcium; D005998:Glycine