Cytokine-mediated suppression of cytochrome P450 1A1 in Hepa-1c1c7 cells by pokeweed mitogen

This study investigated the effects of pokeweed mitogen (PWM) on the regula tion of cytochrome P450 (P450) 1A1 expression in an in vitro model, using m urine hepatoma cell line Hepa-1c1c7 and murine macrophage cell line RAW 264 .7 cell cultures. PWM added directly to Hepa-1c1c7 cells had no effect on 2 ,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced P450 1A1-specific 7-ethox yresorufin O-deethylase (EROD) activity. However, TCDD-induced EROD activit y and P450 1A1 mRNA levels were markedly suppressed when Hepa-1c1c7 cells w ere cultured with PWM-treated conditioned media from RAW 264.7 in a dose-de pendent manner. Concomitant treatment with PWM and pentoxifylline, a TNF al pha synthesis inhibitor, to RAW 264.7 cells decreased the suppressive effec ts of PWM on TCDD-induced EROD activity. In PWM-exposed RAW 264.7 cell cult ures, TNF alpha. and IL-6 levels increased in a dose-dependent fashion. Whe n antibodies to TNF alpha or/and IL-6 were added to PWM-treated conditioned media from RAW 264.7, the suppression of EROD activity was inhibited. Thes e results suggested the suppression of P450 1A1 by PWM was mediated exclusi vely by TNF alpha and IL-6, released from macrophages. (C) 2001 Elsevier Sc ience Ireland Ltd. All rights reserved.