The Induction of Hepatic Cytochrome P4501A Subfamily Enzymes by Nitroanisidines: Species Difference among Experimental Rodents

Abstract

Species differences in the induction of hepatic cytochrome P4501A (CYP1A) subfamily enzymes by nitroanisidines, such as 2-methoxy-4-nitroaniline (2-MeO-4-NA), 2-methoxy-5-nitroaniline (2-MeO-5-NA), and 4-methoxy-2-nitroaniline (4-MeO-2-NA), were investigated among male F344 rats, C57BL/6 Cr mice, and Hartley guinea pigs. All species of animals were treated with a single intraperitoneal injection of each chemical (0.44 mmol/kg body weight), and changes in hepatic microsomal activities for methoxyresorufin O-demethylation (MROD) and ethoxyresorufin O-deethylation (EROD), which were mainly catalyzed by CYP1A2 and CYP1A1, respectively, were examined. Gene expression levels of hepatic CYP1A subfamily enzymes were also examined by a reverse transcription-polymerase chain reaction (RT-PCR) method. These results indicated that all the chemicals examined showed abilities to induce hepatic CYP1A subfamily enzymes in rats but not in the other examined animal species. In the rat liver, the abilities of the chemicals to induce microsomal MROD activity and CYP1A2 gene expression were in the order 2-MeO-4-NA > 2-MeO-5-NA > 4-MeO-2-NA, whereas their abilities to induce microsomal EROD activity and CYP1A1 gene expression were in the order 4-MeO-2-NA > 2-MeO-5-NA > 2-MeO-4-NA. These findings demonstrate for the first time that there are species differences in the induction of hepatic CYP1A subfamily enzymes by the nitroanisidine isomers among rats and other rodents, mice, and guinea pigs.