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

Sulfur dioxide (SO(2)) and benzo(a)pyrene (B(a)P) are common industrial and environmental contaminants. However, few data are available on the effects of SO(2) on proto-oncogenes and tumor suppressor genes, as well as the interactions between SO(2) and other xenobiotics regulating proto-oncogenes or tumor suppressor genes expression. To investigate the interactions between SO(2) and B(a)P, male Wistar rats were exposed to intratracheally instilled with B(a)P or SO(2) 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 SO(2) 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 SO(2) except c-fos expression. Furthermore, SO(2) + 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 SO(2) or B(a)P alone. However, no synergistic effects were observed on H-ras and CYP1A1/2 after SO(2) + B(a)P exposure. Our findings indicate that multiple cell cycle regulatory proteins play key roles in the toxicity of SO(2) 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.