The cytotoxic activity of hematoheme: evidence for two different mechanisms.
Hematoheme displays a potent cytolytic activity toward erythrocytes either in the presence of hydrogen peroxide and a halide ion (system I) or in the presence of oxygen and a reducing agent (system II). In system I it resembles the cytotoxic activity of various peroxidases, whereas in system II it resembles the destructive activity of bleomycin and a variety of metal complexes. Both types of reactions presumably involve the generation of active oxygen species, which are responsible for the damaging effects. In a first attempt to compare the chemical mechanisms of the two types of reactions we used various traps and scavengers of active oxygen species. Tryptophan as well as tyrosine and uric acid were found to be potent inhibitors of the hematoheme-H2O2-halide reaction but do not significantly inhibit the hematoheme-O2-ascorbate reaction. Pyridine, on the other hand, inhibits the oxygen-mediated reaction, but does not affect the peroxide-halide-mediated activity. The cytolytic activity of photoactivated hematoporphyrin, which involves the generation of singlet oxygen, is activated by pyridine and is strongly inhibited by diphenylisobenzofuran. The latter compound is a weak activator of both hematoheme reactions. We conclude that the two hematoheme reactions proceed by two different mechanisms and probably generate different toxic intermediates. The results further suggest that the toxic intermediate generated by photoactivated hematoporphyrin (singlet oxygen) does not play a dominant role in either of the two hematoheme reactions.
D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D003545:Cysteine / Q000494:pharmacology; D006415:Hematoporphyrins / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007454:Iodides / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D011817:Rabbits; D014364:Tryptophan / Q000494:pharmacology; D014527:Uric Acid / Q000494:pharmacology
D006415:Hematoporphyrins; D007454:Iodides; C052066:hematoheme; D014527:Uric Acid; D014364:Tryptophan; D006861:Hydrogen Peroxide; D003545:Cysteine; D001205:Ascorbic Acid; D010100:Oxygen