The 21-aminosteroid inhibitors of lipid peroxidation: Reactions with lipid peroxyl and phenoxy radicals

Abstract The 21-aminosteroids U74006F and U74500A have been examined for their ability to scavenge the lipid peroxyl (LOO·) and phenoxy (phO·) radicals. Lipid peroxidation was followed by measuring the formation of linoleic acid hydroperoxide (LOOH; 18:200H) from linoleic acid during incubations in methanol at 37°C. Initiation of lipid peroxidation was by the radical generator 2,2'-azobis(2,4-dimethylvaleronitrile; AMVN), which under the conditions employed, initiated LOOH formation at a constant rate of 22 μM/h with a kinetic chain length of 21. Alpha-tocopherol (αTC) nearly completely blocked the chain reaction by scavenging LOO·, reducing its formation to that essentially attributable to initiation alone. The average inhibition rate constant k inh for αTC at 37°C was calculated as 4.9 × 10 5 M −1 sec −1 . U74006F or U74500A also inhibited LOOH formation, reducing its rate to a constant fraction of control in a concentration dependent manner. U74500A also inhibited LOOH formation, reducing of LOO· than U74006F; however, both compounds were considerably less potent than αTC based upon their respective k inh 's at 37°C. Similarly, αTC, U74006F and U74500A scavenged PhO·. As seen with LOO· scavenging, αTC was orders of magnitude more reactive toward PhO· than either 21-aminosteroid as judged by their respective second order rate constants ( k 2 ). Both U74006F and U74500A were degraded during their reaction with LOO· or PhO· to as yet uncharacterized product(s). The data indicate that while the 21-aminosteroids can scavenge lipid radicals, their activity in this regard is less than expected based upon their ability to inhibit iron dependent lipid peroxidation.