FUNCTIONAL ROLE OF CYTOCHROME P-450 2A3 IN N -NITROSOMETHYLBENZYLAMINE METABOLISM IN RAT ESOPHAGUS

Previous in vitro studies demonstrated that the rat esophageal carcinogen N -nitrosomethylbenzylamine (NMBA) is metabolically activated by cytochrome P-450s (CYP) 2A3 and 2E1. However, the in vivo role of these P-450s in the metabolism of NMBA has not been fully evaluated. In this study, the effects of single and multiple doses of NMBA were investigated on CYP2A3 and CYP2E1 mRNA expression in the rat esophagus and lung. Seven- to 8-wk old male Fischer 344 rats were administered a single subcutaneous dose of NMBA at either 0.5 mg/kg or 2 mg/kg body weight, after which the rats were sacrificed at 1, 3, 6, 12, 24, 48, and 72 h. In the multiple-dose experiment, 2 groups of rats were dosed with 0.5 mg/kg body weight NMBA 3 times per week for 1 wk or 3 wk. The animals were sacrificed 24 h following the last treatment. Semiquantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis demonstrated a reduction of CYP2A3 mRNA expression in lung and esophagus from NMBA-treated animals compared to di...