NADH-dependent reductive stress and ferritin-bound iron in allyl alcohol-induced lipid peroxidation in vivo: the protective effect of vitamin E.
The role of iron in allyl alcohol-induced lipid peroxidation and hepatic necrosis was investigated in male NMRI mice in vivo. Ferrous sulfate (0.36 mmol/kg) or a low dose of ally alcohol (0.6 mmol/kg) itself caused only minor lipid peroxidation and injury to the liver within 1 h. When FeSO4 was administered before allyl alcohol, lipid peroxidation and liver injury were potentiated 50-100-fold. Pretreatment with DL-tocopherol acetate 5 h before allyl alcohol protected dose-dependently against allyl alcohol-induced lipid peroxidation and liver injury in vivo. Products of allyl alcohol metabolism, i.e. NADH and acrolein, both mobilized trace amounts of iron from ferritin in vitro. Catalytic concentrations of FMN greatly facilitated the NADH-induced reductive release of ferritin-bound iron. NADH effectively reduced ferric iron in solution. Consequently, a mixture of NADH and Fe3+ or NADH and ferritin induced lipid peroxidation in mouse liver microsomes in vitro. Our results suggest that the reductive stress (excessive NADH formation) during allyl alcohol metabolism can release ferrous iron from ferritin and can reduce chelated ferric iron. These findings provide a rationale for the strict iron-dependency of allyl alcohol-induced lipid peroxidation and hepatotoxicity in mice in vivo and document iron mobilization and reduction as one of several essential steps in the pathogenesis.
Jaeschke
H
H
Institute of Physiological Chemistry, University of Tübingen, Germany.
Kleinwaechter
C
C
Wendel
A
A
D000433:1-Propanol / Q000494:pharmacology; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005293:Ferritins / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction; D020005:Propanols; D014810:Vitamin E / Q000494:pharmacology*
D005227:Fatty Acids; D020005:Propanols; D009243:NAD; D014810:Vitamin E; C006463:allyl alcohol; D005293:Ferritins; D000433:1-Propanol; D007501:Iron; D000410:Alanine Transaminase