| Abstrakt: |
Propylene oxide (PO) is a relatively weak mutagen that induces nasal tumor formation in rats during long-term inhalation studies at high exposures (≥300 p.p.m.), concentrations that also cause cytotoxicity and increases in cell proliferation. Direct alkylation of DNA by PO leads mainly to the formation of N7-(2-hydroxypropyl)guanine (7-HPG). In this study, the accumulation of 7-HPG in tissues of male F344 rats exposed to 500 p.p.m. PO (6 h/day, 5 days/week for 4 weeks) by the inhalation route was measured by gas chromatography–high resolution mass spectrometry (GC-HRMS). In animals killed up to 7 h following the end of the last exposure the levels of 7-HPG (pmol/μmol guanine) in nasal respiratory tissue, nasal olfactory tissue, lung, spleen, liver and testis DNA 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 amounts of 7-HPG in the same tissues of animals killed 3 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. A comparable rate of disappearance of 7-HPG was found among all tissues. DNA from lymphocytes pooled from four rats killed at the end of the last exposure was found to have 39.6 pmol adduct/μmol guanine. Quantitation of DNA apurinic/apyrimidinic sites, potentially formed after adduct loss by chemical depurination or DNA repair, showed no difference between tissues from control and exposed rats. The level of N-(2-hydroxypropyl)valine in hemoglobin of exposed rats was also determined using a modified Edman degradation method followed by GC-HRMS analysis. The value obtained was 90.2 ± 10.3 pmol/mg globin. These data demonstrate that nasal respiratory tissue, which is the target tissue for carcinogenesis, has a much greater level of alkylation of DNA than non-target tissues. |
