Radical formation during the peroxidase catalyzed metabolism of carcinogens and xenobiotics: the reactivity of these radicals with GSH, DNA, and unsaturated lipid

Abstract

Radicals generated by the peroxidase catalyzed oxidation of a wide variety of substrates oxidize GSH, NADH, or arachidonate with accompanying oxygen activation. Substrates studied include carcinogens, drugs, or xenobiotics. The effectiveness of the various radicals is partly related to their one-electron oxidation potential. High redox potential radicals were particularly effective at oxidizing these biomolecules. Low redox potential radicals did not react with GSH, NADH, or arachidonate, but can directly activate oxygen to form hydroxyl radicals or undergo scission to carbon radicals. The hydroxyl and carbon radicals have a high redox potential and readily oxidize biomolecules. DNA strand breakage also occurs with some high redox potential radicals, but DNA did not react with low redox potential radicals. The extensive binding of xenobiotics to DNA in the peroxidase system was attributed to noncovalent binding by polymeric products or covalent binding by the two electron oxidation product (formed by radical dismutation or oxidation). The latter can cause alkali labile DNA strand breaks. GSH conjugate formation was also attributed to the two electron oxidation product. Radicals have been trapped in intact cells and oxygen activation or lipid peroxidation has been demonstrated but it is still not clear whether the associated GSH oxidation, DNA strand breakage and cytotoxicity is the result of direct action by radicals. Indirect enzymic mechanisms for free radical mediated DNA strand breakage and cytotoxicity are discussed.