Paracetamol Metabolism in the Rat: Relationship to Covalent Binding and Hepatic Damage

Abstract

1. The degree of liver damage observed 48 h after administration of 14C ring-labelled paracetamol (3-23 mmol/kg) to rats was proportional to the amount of a highly reactive metabolite retained in the liver, bound covalently to hepatocellular proteins. 2. With increasing doses of paracetamol, urinary excretion of the glucuronide and sulphate conjugates reached a plateau, whereas the output of cysteine and mercapturic acid conjugates increased markedly. 3. The degree of covalent binding at 48 h was proportional to the rate of urinary elimination of these two latter conjugates in the first 24 h after dosing.

1-Aminobenzotriazole, a Known Cytochrome P450 Inhibitor, Is a Substrate and Inhibitor ofN-Acetyltransferase

“…Acetaminophen and 7-hydroxycoumarin have been reported to be metabolized primarily through glucuronidation and sulfation in the rat (Davis et al, 1976;Wang et al, 2005). UGT activity was determined in RLM (4 mg/ml), using acetaminophen (2 M) or 7-hydroxycoumarin (50 M) as substrates.…”

The metabolism and toxicity of paracetamol in Sprague-Dawley and wistar rats

“…The same trend may also be seen by comparing our data with that of Jollow et al (7) who used male Sprague-Dawley rats. Again Davis et al (8) have shown that male Wistar rats produce more Female (19) Male (19) Female" Male ( mercapturic acid than do females of that species. In their study they found that males developed grade 2 hepatic necrosis following a dose of 10 mmole/kg (Table XIV).…”

“…The most significant metabolic difference was the trend to decreased PM and increased 3SMeP and 3SMePG. Wistar rats were included in this study since other authors (8,19) have referred to their handling of paracetamol and thus they provide interesting controls for Sprague-Dawley rats. Furthermore they are required as controls in studies of the metabolism of paracetanol in Gunn rats (26) which are a mutant strain of Wistars.…”

“…The metabolic events leading to acute centrilobular hepatic necrosis in humans and experimental animals following paracetamol overdose have been extensively studied (7,8). Accordingly, a mechanism has been proposed (9) by which a reactive paracetamol metabolite is formed via a cytochrome P 450 dependent mixed function oxidase.…”

“…metabolism, paracetamol mercupturic acid (PM) and the cysteine conjugate (PC) become significant as the dose increases. Since these metabolites were quantitated (7,8) other metabolites have been reported. Thus Andrews et al (16) found the sulphate and glucuronide conjugates of 3-methoxyparacetamol (30MePS,G) as well as the 3-0-sulphate conjugate of the unmethylated analogue 3-hydroxyparacetamol (30SP).…”