Sulfur dioxide and benzo(a)pyrene modulates CYP1A and tumor-related gene expression in rat liver

Abstract

Sulfur dioxide (SO2) and benzo(a)pyrene (B(a)P) are common industrial and environmental contaminants. However, few data are available on the effects of SO2 on proto-oncogenes and tumor suppressor genes, as well as the interactions between SO2 and other xenobiotics regulating proto-oncogenes or tumor suppressor genes expression. To investigate the interactions between SO2 and B(a)P, male Wistar rats were exposed to intratracheally instilled with B(a)P or SO2 inhalation alone or together. We detected mRNA expression of CYP1A1 and 1A2, 7-ethoxyresorufin O-deethylase (EROD), and methoxyresorufin O-demethylase (MROD) activities in livers. The mRNA and protein levels of several cancer-related genes were analyzed in livers by real-time RT-PCR and Western blot, respectively. The EROD/MROD activities and CYP1A1/2 expression were down-regulated by SO 2 but up-regulated by B(a)P alone. Exposure of SO2 alone induced c-fos, c-jun, c-myc, H-ras, and p53 expression, and depressed p16 and Rb expression in livers. The effects of B(a)P on the above gene were similar to SO2 except c-fos expression. Furthermore, SO2 + B(a)P exposure increased the expression of c-fos, c-jun, c-myc, and p53, and decreased p16 and Rb expression in livers compared with exposed to SO2 or B(a)P alone. However, no synergistic effects were observed on H-ras and CYP1A1/2 after SO2 + B(a)P exposure. Our findings indicate that multiple cell cycle regulatory proteins play key roles in the toxicity of SO2 and B(a)P in livers. It might involve the activation of c-fos, c-jun, c-myc, and p53. And p16-Rb pathway might also participate in the progress. Although the gene products we studied are classed as oncogenes and tumor suppressor genes, their functions actually relate to more general processes of control of cell proliferation, survival, and/or apoptosis. © 2009 Wiley Periodicals, Inc.