Propylene oxide carcinogenesis: Roles of DNA adduct accumulation and DNA replication, and the assessment of hemoglobin adducts as biomarkers of exposure.

摘要

Propylene oxide (PO) caused nasal tumors in rats at concentrations (≥300 ppm) that also caused increases in respiratory cell hyperplasia. The mechanism by which PO caused tumors is not known but information on the relationship between DNA damage, cell proliferation and neoplasia should help understand the events involved in PO carcinogenesis. N7-(2-hydroxypropyl)guanine (7-HPG) is the major PO DNA adduct. The amount of 7-HPG (pmol/mumol guanine+/-SD) in nasal respiratory epithelium (NRE), nasal olfactory epithelium, lung, spleen, liver, and testis of rats exposed to 500 ppm PO for 20 days were 606.2 +/- 53.0, 297.5 +/- 56.5, 69.8 +/- 3.8, 43.0 +/- 3.8, 27.5 +/- 2.4 and 14.2 +/- 0.7, respectively. The levels of 7-HPG in the same tissues of animals sacrificed three days after cessation of exposure were 393.3 +/- 57.0, 222.7 +/- 29.5, 51.5 +/- 1.2, 26.7 +/- 1.0, 18.0 +/- 2.6, and 10.4 +/- 0.1. Analysis of control tissues showed no evidence of endogenous formation of 7-HPG. These data demonstrate that the NRE, which is the target tissue for carcinogenesis, has a much greater level of alkylation of DNA than non-target tissues. Studies on cell proliferation, 7-HPG accumulation in tissues, and N-(2-hydroxypropyl)vabne (N-HPVal) accumulation in globin (Hb) were done in rats exposed to 0, 5, 25, 50, 300 or 500 ppm PO for 3 or 20 days. Significant increases in cell proliferation were observed in the NRE lining the anterior nasal passages at exposures of 300 and 500 ppm (>3.6 fold) for both exposure periods. 7-HPG accumulation in NRE, lung and liver, and N-HPVal accumulation in globin were linearly dependent on concentration for both exposure periods. The nose had the highest concentration of DNA adducts followed by lung and liver. The data obtained demonstrated that PO Hb adducts are good biomarkers of exposure but that they cannot predict differences in DNA adduction between directly and systemically exposed tissues, and that NRE 7-HPG accumulation does not correlate with the exposure response for tumor formation but that PO-induced cell proliferation, that is only present at the highest two concentrations of PO, may be a critical factor for tumorigenesis in this tissue.