REDOX MEDIATION IN THE PEROXIDASE-CATALYZED OXIDATION OF AMINOPYRINE - POSSIBLE IMPLICATIONS FOR DRUG-DRUG INTERACTIONS

Many drugs, industrial pollutants, and other xenobiotics are known to be oxidized by peroxidases to potentially harmful free-radical interme diates. We have examined the possibility that certain compounds, actin g as efficient peroxidase substrates, may stimulate the formation of r eactive free radicals by acting as mediators of electron transfer reac tions (redox mediators). To explore this hypothesis, we have investiga ted the interaction of two well-known peroxidase substrates, chlorprom azine and aminopyrine. As shown by ESR and UV-visible spectroscopy, ch lorpromazine radical was able to oxidize aminopyrine to aminopyrine ca tion radical. The rate constant for this rapid, pH-dependent, reaction was estimated to be 1 x 10(7) M(-1) s(-1) at pH 4.5. Transient-state and steady-state kinetic studies both showed that rate constants for c hlorpromazine oxidation to its cation radical by horseradish peroxidas e (HRP) were about 100-fold greater than for the corresponding HRP-cat alyzed oxidation of aminopyrine to its cation radical. When both amino pyrine and chlorpromazine mere present with HRP and H2O2, aminopyrine cation radical formation was stimulated 100-fold. Concomitantly, the a ccumulation of chlorpromazine cation radical was completely inhibited in the presence of aminopyrine. Similar results were obtained when lac toperoxidase, myeloperoxidase, or the myeloperoxidase mimic HOCl were substituted for HRP. These data suggest that chlorpromazine can act as a redox mediator for peroxidase-catalyzed oxidation of aminopyrine an d other chemicals. We suggest that some peroxidase substrates, acting as redox mediators, may stimulate the production of toxic free-radical intermediates from various drugs and other xenobiotics. As such, this may have implications for a number of adverse effects caused by these xenobiotic chemicals.