Microsomal reduction of low-molecular-weight Fe3+ chelates and ferritin: enhancement by adriamycin, paraquat, menadione, and anthraquinone 2-sulfonate and inhibition by oxygen.
Reduction of iron is important in promoting xenobiotic-enhanced, microsomal lipid peroxidation, yet there is little evidence that Fe3+ chelates that promote lipid peroxidation can be reduced by the microsomal system. We have shown that rat liver microsomes catalyse NADPH-dependent reduction of Fe3+ without chelator, as well as Fe3+(ADP), Fe3+(ATP), Fe3+(citrate), Fe3+(EDTA), and ferrioxamine in N2. The NADPH oxidation that accompanied Fe3+ reduction was inhibited by CO for all chelates, except Fe3+ (EDTA). This implies that, except for Fe3+ (EDTA), cytochrome P450 was involved in reduction of the complexes. Adriamycin, paraquat, and anthraquinone 2-sulfonate (AQS) enhanced reduction of all the Fe3+ chelates, whereas menadione enhanced reduction only of Fe3+(ADP) and Fe3+(citrate). All the compounds enhanced oxidation of NADPH in the presence or absence of iron. This was not inhibited by CO, and the results are compatible with Fe3+ reduction occurring via the xenobiotic radicals produced by cytochrome P450 reductase. Microsomal reduction of the xenobiotics, except menadione, enabled the reduction and release of iron from ferritin. Fe3+ chelate reduction, both with and without xenobiotic, was inhibited by O2, although it still proceeded in air at 10-20% of the rate in N2. Iron-dependent lipid peroxidation was promoted by ADP and ATP, inhibited 50% by citrate, and completely inhibited by EDTA and desferrioxamine. Of the xenobiotics, only Adriamycin enhanced microsomal lipid peroxidation. These results indicate that the effects of chelators and xenobiotics on Fe3+ reduction do not correlate with lipid peroxidation and, although reduction is necessary, there must be other factors involved.
Vile
G F
GF
Department of Pathology, Christchurch School of Medicine, Christchurch Hospital, New Zealand.
Winterbourn
C C
CC
D000693:Anaerobiosis; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D005293:Ferritins / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism*; D008054:Lipid Peroxides / Q000096:biosynthesis; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology*; D010269:Paraquat / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014812:Vitamin K / Q000494:pharmacology*
D000880:Anthraquinones; D003574:Cytochrome c Group; D007502:Iron Chelating Agents; D008054:Lipid Peroxides; D014812:Vitamin K; C023554:anthraquinone sulfonate; D009249:NADP; D004317:Doxorubicin; D005293:Ferritins; D010269:Paraquat; D010100:Oxygen