Properties of the radicals formed by one-electron oxidation of acetaminophen--a pulse radiolysis study.

The semi-iminoquinone radical of acetaminophen, which has previously been proposed as a possible hepatotoxic intermediate in the cytochrome P-450 catalysed oxidation of acetaminophen, has been generated and studied by pulse radiolysis. In the absence of other reactive solutes, the radical decays rapidly by second order kinetics with a rate constant (2k2) of (2.2 +/- 0.4) x 10(9) M-1 sec-1. In alkaline solutions the radical deprotonates with a pK of 11.1 +/- 0.1 to form a radical-anion, as confirmed by the effect of ionic strength on the rate of radical decay. The acetaminophen radical-anion reacts with resorcinol at high pH values, leading to the formation of a transient equilibrium from which the one-electron reduction potential of the semi-iminoquinone radical of acetaminophen is estimated to be +0.707 +/- 0.01 V at pH 7. This value predicts that acetaminophen should be oxidised by thiyl radicals. This was confirmed by pulse radiolysis experiments for reaction of the cysteinyl radical, for which rate constants of 7 x 10(6) M-1 sec-1 at pH 7 and 2.7 x 10(8) M-1 sec-1 at pH 11.3 were obtained. The reaction of O2 with the acetaminophen semi-iminoquinone radical could not be detected by pulse radiolysis, and alternative mechanisms for superoxide radical formation are discussed.