Mn. Rios-blanco et al., Quantitation of DNA and hemoglobin adducts and apurinic/apyrimidinic sitesin tissues of F344 rats exposed to propylene oxide by inhalation, CARCINOGENE, 21(11), 2000, pp. 2011-2018
Propylene oxide (PO) is a relatively weak mutagen that induces nasal tumor
formation in rats during long-term inhalation studies at high exposures (gr
eater than or equal to 300 p.p.m.), concentrations that also cause cytotoxi
city and increases in cell proliferation. Direct alkylation of DNA by PO le
ads mainly to the formation of N7-(2-hydroxypropyl)guanine (7-MHPG). In thi
s 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 3 weeks) by the inhalation route wa
s 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 l
evels of 7-HPG (pmol/mu mol guanine) in nasal respiratory tissue, nasal olf
actory 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, resp
ectively. 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 disa
ppearance 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/mu mol guanine, Quantitation of DNA apurinic/apyrimidinic si
tes, potentially formed after adduct loss by chemical depurination or DNA r
epair, showed no difference between tissues from control and exposed rats.
The level of N-(2-hydroxypropyl)valine in hemoglobin of exposed rats was al
so determined using a modified Edman degradation method followed by GC-HRMS
analysis. The value obtained was 90.2 +/- 10.3 pmot/mg globin, These data
demonstrate that nasal respiratory tissue, which is the target tissue for c
arcinogenesis, has a much greater level of alkylation of DNA than non-targe
t tissues.