Studies on the mechanism of paracetamol-induced protection against paracetamol hepatotoxicity

Abstract

In rats, 3 days treatment with paracetamol (1 oral dose of 1 g/kg daily) produced a complete protection against the hepatotoxic actions of a further dose of paracetamol as documented by determination of serum enzyme activities (gluatmic-oxaloacetic transaminase, (GOT), glutamic-pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), bromsulphthalein retention and histological investigations. Subacute paracetamol treatment decreased liver gluatthione levels by 46%, liver microsomal cytochrome P-450 content by 23%, hepatic hydroxylation of aniline by 19% and hepatic demethylation of aminopyrine by 46%. it afforded also some protection against the hepatotoxic actions of carbon tetrachloride, bromobenzene and thiocetamied, but did not influence the antiphlogistic activity of paracetamol (carrageebab paw edema test). Plasma and liver concentrations of free paracetamol after oral administration of 1 g/kg paracetamol were somewhat higher in the subcutely paracetamol-pretreated rats than in the non-pretreated control animals whereas no differences in the concentrations of conjugated paracetamol were found between the 2 groups. Pretreatment with paracetamol did not influence the urinary excretion of free paracetamol but caused some shift in the urinary excretion of paracetamol conjugates: pretreated rats excreted 23% less of the paracetamol glucuronide and sulfate and 33% more of the paracetamol mercapturate that the control animals. A depression of the microsomal mixed-function oxidase activity is presumed to be the main cuase of the paracetamol-induced protection against paracetamol hepatotoxicity.