Metavanadate causes cellular accumulation of copper and decreased lysyl oxidase activity.
Selected indices of copper metabolism in weanling rats and fibroblast cultures were progressively altered in response to increased levels of sodium metavanadate. In diets, vanadium was added in amounts ranging from 0 to 80 microg V/g of diet, that is, 0-1.6 micromol V/g of diet. In fibroblast cultures, vanadium ranged from 0 to 400 nmol V/ml. The inhibition of P-ATPase-7A activity by metavanadate, important to copper egress from cells, was a primary focus. In skin, and tendon, the copper concentration was increased in response to increased dietary levels of metavanadate, whereas lysyl oxidase activity, a secreted cuproprotein, was reduced. The reduction in lysyl oxidase activity was also accompanied by reduced redox cycling potential of isolated fractions of lysyl oxidase, presumably due to reduced lysyltyrosyl quinone (LTQ) formation at the active site of lysyl oxidase. In contrast, liver copper concentrations and plasma ceruloplasmin activity were not affected by metavanadate exposure. However, semicarbazide-sensitive benzylamine oxidase (SCBO) activity, which was taken as an indirect measure of vascular adhesive protein-1 (VAP-1), was increased. In cultured fibroblasts, cellular copper was also increased and lysyl oxidase decreased in response to metavanadate. Moreover, the steady-state levels of atp7a and lysyl oxidase mRNAs were not affected by addition of metavanadate to culture medium up to 200 nmol/ml. Taken together, these data suggest that pathways involving copper egress and lysyl oxidase activation are particularly sensitive to metavanadate exposure through processes that are predominately posttranslational.
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M561X5.
Changtai T
CT
Cui
Janet Y
JY
Uriu-Adams
Eskouhie H
EH
Tchaparian
Carl L
CL
Keen
Robert B
RB
Rucker
D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D002570:Ceruloplasmin / Q000187:drug effects* / Q000378:metabolism; D003300:Copper / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014638:Vanadates / Q000008:administration & dosage / Q000633:toxicity*
D004791:Enzyme Inhibitors; D014638:Vanadates; D003300:Copper; D002570:Ceruloplasmin; D008249:Protein-Lysine 6-Oxidase