Acetaminophen Produces Cataract in DBA2 Mice by Ah Receptor-Independent Induction of CYP1A2

ABSTRACT

The metabolic transformation of acetaminophen to N-acetyl-p-benzoquinone imine by cytochrome P450 enzymes(e.g., cytochrome P450 1A2)is a prerequisite for acetaminopheninduced cataract formation in mice. Aromatic hydrocarbons, such as β-naphthoflavone, induce cytochrome P450 1A2 in C57BL6 mice via the mediation of the aromatic hydrocarbon receptor and render the animals susceptible to cataract formation by acetaminophen administration but not in DBA2 mice which do not respond to cytochrome P450 1A2 induction by these compounds. Polycyclic hydrocarbons, such as acenaphthylene, were recently found to induce cytochrome P450 1A2 gene expression in young DBA2 mice by aromatic hydrocarbon receptor-independent pathways. In this work, we investigated whether enhanced metabolism of acetaminophen to N-acetyl-p-benzoquinone by cytochrome P450 1A2 induction by acenaphthylene could produce cataract in young DBA2 mice. Fifteen-day-old DBA2 mice were pretreated with two intraperitoneal injections of acenaphthylene and, 24 hr later, with one injection of acetaminophen. In most mice, cataract developed 18-24 hr after acenaphthylene injection. Acenaphthylene treatment of young DBA2 mice resulted in a 2-fold increase in cytochrome P450 1A2-dependent methoxyresorafin O-demethylase activity in the liver. These results support the hypothesis that the aromatic hydrocarbon receptor-independent induction of cytochrome P450 1A2 enzyme leads to accumulation of sufficient N-acetyl-p-benzoquinone in the liver and cataract development in the eye.