Comparative Activation of Paracetamol in the Rat, Mouse and Man

Abstract

The minor analgesic paracetamol is relatively non-toxic at normal therapeutic doses. In overdose it is hepatotoxic in a number of species, including man, due to its conversion to a highly reactive intermediate, N-acetyl-p-benzoquinoneimine (NABQI), by the hepatic mixed function oxidase system (reviewed in Prescott 1983). There are marked differences in susceptibility to the hepato toxicity of paracetamol, both within and between species (Davis et al. 1974). The causes of this variation are largely attributable to differences in the extent to which paracetamol is converted to NABQI, i.e. to differences in the activity of cytochrome P₄₅₀ (Davis et al. 1974; Green et al. 1984). However, the factors responsible for regulating the forms of cytochrome P₄₅₀ involved in this reaction have yet to be identified. Certainly, environmental factors play some role. For example, chronic ingestion of ethanol alters the activation and hence the toxicity of paracetamol in laboratory animals (Peterson 1983) and possibly in man (Prescott 1983). The extent to which genetic factors contribute to interindividual differences in this reaction is still far from clear. The present study was conducted to investigate some of the possible causes of inter- and intraspecies differences in paracetamol activation and also to attempt to identify the specific forms of cytochrome P₄₅₀ involved.