416 THE TOXICITY OF ACETAMINOPHEN ANALOGUES IN LYMPHOCYTE CULTURE

Abstract

Acetaminophen (A4AP) is known to be activated by oxidative metabolism to a reactive iminoquinone. Two structural analogues, N-Acetyl-3-AminoPhenol (A3AP) and N-Acetyl-2-AminoPhenol (A2AP) have been studied as to their oxidation. A2AP is more reactive than A4AP whereas A3AP is not oxidizable to an iminoquinone using an electrochemical cell. Using the in vitro human lymphocyte/mouse hepatic microsome method which demonstrated toxicity of A4AP we have shown that A2AP is a more potent cytotoxic agent than A4AP and that A3AP is devoid of toxicity (Table). This is consistent with the observation that A3AP is not hepatotoxic in animals but contradicts the observation that A2AP was also not hepatotoxic. Previous arguments as to the necessity for N-hydroxylation to activate A4AP to a reactive species are not substantiated by these observations. A2AP, not hydroxylated due to steric constraints, is readily oxidized and is very cytotoxic. Its apparent lack of toxicity in animals was likely an artifact of its rapid clearance in vivo. A3AP, the non-toxic analogue in vitro and in vivo, represents an interesting alternative to A4AP as a new therapeutic agent.

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