ABSTRACT:Dichloromethane (DCM) is metabolically converted to carbon monoxide mostly by CYP2E1 in liver, resulting in elevation of blood carboxyhemoglobin (COHb) levels. We investigated the effects of a subtoxic dose of acetaminophen (APAP) on the metabolic elimination of DCM and COHb elevation in adult female rats. APAP, at 500 mg/kg i.p., was not hepatotoxic as measured by a lack of change in serum aspartate aminotransferase, alanine aminotransferase, and sorbitol dehydrogenase activities. In rats pretreated with APAP at this dose, the COHb elevation resulting from administration of DCM (3 mmol/kg i.p.) was enhanced significantly. Also blood DCM levels were reduced, and its disappearance from blood appeared to be increased. Hepatic CYP2E1-mediated activities measured with chlorzoxazone, p-nitrophenol, and p-nitroanisole as substrates were all induced markedly in microsomes of rats treated with APAP. Aminopyrine N-demethylase activity was also increased slightly, but significantly. Western blot analysis showed that APAP treatment induced the expression of CYP2E1 and CYP3A proteins. Neither hepatic glutathione contents nor glutathione S-transferase activity was changed by the dose of APAP used. The results indicate that, contrary to the well known hepatotoxic effects of this drug at large doses, a subtoxic dose of APAP may induce CYP2E1, and to a lesser degree, CYP3A expression. This is the first report that APAP can increase cytochrome P450 (P450)-mediated hepatic metabolism and the resulting toxicity of a xenobiotic in the whole animal. The pharmacological/toxicological significance of induction of P450s by a subtoxic dose of APAP is discussed.Acetaminophen (APAP), a widely used analgesic-antipyretic, may cause severe liver and kidney injuries at large or chronic doses. The APAP-mediated cellular injury is primarily initiated by metabolic conversion of this drug into a reactive intermediate, N-acetyl-p-benzoquinoneimine. It has been demonstrated that multiple forms of cytochrome P450 (P450) including CYP2E1, 1A2, and 3A4 are implicated in the activation of APAP to the reactive metabolite (Raucy et al., 1989;Patten et al., 1993;Zaher et al., 1998), but most investigators accept the fact that CYP2E1 has a principal role in the oxidative metabolism of this drug both in humans and rodents. The reactive metabolite is normally detoxified by conjugation with glutathione (GSH). Therefore, the hepatotoxicity of APAP is mainly dependent on the metabolic activities responsible for the activation of this drug and the effectiveness of GSH conjugation reaction.Dichloromethane (DCM, CH 2 Cl 2 ) is widely used in industry as a degreaser, as a solvent, as an extraction medium, and also as an important constituent of paint removers. Unlike its chemical congeners, such as carbon tetrachloride and chloroform, that are potent hepatotoxins, the liver toxicity of this substance is negligible (Nitschke et al., 1988). Instead, DCM is metabolically converted to carbon monoxide (CO) by CYP2E1 (Guengerich et al., 1991;Kim and Kim, 1996;Wi...