In Vivo Mechanisms of Tissue-Selective Drug Toxicity: Effects of Liver-Specific Knockout of the NADPH-Cytochrome P450 Reductase Gene on Acetaminophen Toxicity in Kidney, Lung, and Nasal Mucosa

Abstract

Acetaminophen overdose causes toxicity in liver and extrahepatic tissues. Although it is well established that cytochrome P450 enzymes play a critical role in the metabolic activation of acetaminophen, it is not yet clear whether acetaminophen toxicity in extrahepatic tissues is a consequence of hepatic biotransformation. The aim of this study was to determine whether extrahepatic acetaminophen toxicity is altered in a mouse model that has liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene. Liver-specific Cpr-null (Null) mice were resistant to acetaminophen hepatotoxicity, and they showed faster acetaminophen clearance than did wild-type mice at a toxic acetaminophen dose (400 mg/kg i.p.). However, when circulating acetaminophen levels were made equivalent in the two strains, the severity of extrahepatic acetaminophen toxicity was decreased in the Null relative to that in the wild-type mice in the lung, kidney, and lateral nasal glands, although not in the nasal olfactory and respiratory mucosa. In the lung and liver, the decreased acetaminophen toxicity was accompanied by substantial decreases in the formation of acetaminophen-protein adducts in the Null mice; adducts were not detected in other tissues examined. These results indicate that acetaminophen toxicity in the nasal mucosa is not dependent on hepatic microsomal P450-catalyzed metabolic activation and that acetaminophen toxicity in the lung, kidney, and lateral nasal glands is at least partly caused by liver-derived acetaminophen metabolites.