Paracetamol, 3-monoalkyl- and 3,5-dialkyl derivatives. Comparison of their microsomal cytochrome P-450 dependent oxidation and toxicity in freshly isolated hepatocytes

摘要: The effects of 3-monoalkyl- and 3,5-dialkyl-substitution on the cytotoxicity paracetamol (PAR) in rat hepatocytes was studied. PAR is known to be bioactivated by hepatic microsomal cytochrome P-450 containing a mixed-function oxidase system presumably N-acetyl-para-benzoquinone imine (NAPQI), reactive metabolite which upon overdosage drug causes depletion cellular glutathione (GSH) hepatotoxicity. four 3-mono- 3,5-di-alkyl-substituted derivatives investigated this study (R = CH3, C2H5, C3H7, C4H9) interacted with giving rise reverse type I spectral changes. Like PAR, all underwent P-450-mediated oxidation NAPQIs. In contrast induction phenobarbital, 3-methylcholanthrene enhanced its derivatives. NAPQIs formed from 3-mono-alkyl were found conjugate GSH oxidise GSSG. 3,5-dialkyl-substituted derivatives, however, only oxidized 3-monoalkyl deplete about same extent equally toxic freshly isolated treated rats. contrast, did not affect levels hepatocytes, even at higher concentrations. It suggested that difference between way reacting 3,5-dialkyl-NAPQIs thiols protein could account for observed toxicity 3,5-dialkyl- 3-monoalkyl-substituted PAR.