Abstract
This study investigated the effects of pokeweed mitogen (PWM) on the regulation of cytochrome P450 (P450) 1A1 expression in an in vitro model, using murine 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-ethoxyresorufin O-deethylase (EROD) activity. However, TCDD-induced EROD activity and P450 1A1 mRNA levels were markedly suppressed when Hepa-1c1c7 cells were cultured with PWM-treated conditioned media from RAW 264.7 in a dose-dependent manner. Concomitant treatment with PWM and pentoxifylline, a TNFα synthesis inhibitor, to RAW 264.7 cells decreased the suppressive effects of PWM on TCDD-induced EROD activity. In PWM-exposed RAW 264.7 cell cultures, TNFα and IL-6 levels increased in a dose-dependent fashion. When antibodies to TNFα or/and IL-6 were added to PWM-treated conditioned media from RAW 264.7, the suppression of EROD activity was inhibited. These results suggested the suppression of P450 1A1 by PWM was mediated exclusively by TNFα and IL-6, released from macrophages.
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