Species variation in the metabolic activation of paracetamol to toxic intermediates: role of cytochromes p-450 and p-448.

The metabolic activation of paracetamol to reactive intermediate(s) covalently bound to microsomes was investigated using microsomal preparations from various laboratory animals and man. The hamster and mouse, in contrast to the rat, were good activators. Microsomal preparations from 3-methylcholanthrene (3MC)-induced hamsters were markedly more efficient in activating paracetamol than similar preparations from phenobarbital (PB)-induced animals. The activation of paracetamol by the 3MC-induced hamster preparations was inhibited by 9-hydroxyellipticine but not by metyrapone. These results indicate that hepatic cytochrome P-448 but not cytochrome P-450 can convert paracetamol to reactive intermediate(s) which bind covalently to microsomal proteins.