IMMUNOCYTOCHEMICAL IDENTIFICATION OF DNA-ADDUCTS, O-6-METHYLGUANINE AND 7-METHYLGUANINE, IN RESPIRATORY AND OTHER TISSUES OF RAT, MOUSE ANDSYRIAN-HAMSTER EXPOSED TO 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE
J. Vanbenthem et al., IMMUNOCYTOCHEMICAL IDENTIFICATION OF DNA-ADDUCTS, O-6-METHYLGUANINE AND 7-METHYLGUANINE, IN RESPIRATORY AND OTHER TISSUES OF RAT, MOUSE ANDSYRIAN-HAMSTER EXPOSED TO 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE, Carcinogenesis, 15(9), 1994, pp. 2023-2029
The present paper reports about an immunocytochemical inventory of the
cell types involved in the metabolic activation of the tobacco-specif
ic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to
a DNA methylating metabolite. The formation and distribution of the m
ethylated DNA bases O-6-methylguanine (O-6-meGua) and 7-methylguanine
(7-MeGua) were studied in respiratory tissues, oesophagus, liver, kidn
eys, pancreas, small intestine, colon and prostate of rat, mouse and h
amster 6 h after treatment with a single dose of 30 mg NNK/kg. The tis
sue- and cell-specific distribution of O-6-meGua- and 7-meGua-specific
nuclear staining showed the same patterns and were remarkably similar
in rat, mouse and hamster in spite of the diverging spectra of MVK-in
duced tumours in these species. In nasal tissue, a target for NNK-indu
ced tumourigenesis in rat and hamster, but not in mouse, adduct-specif
ic nuclear staining was observed in ah three species in sustentacular
cells, Bowman glands, respiratory epithelial cells and serous glands.
Both methylated DNA bases were also observed in basal cells of the olf
actory epithelium of rat and (occasionally) hamster, but not in those
of the mouse. In the trachea, a target for NNK-induced tumourigenesis
in hamster only, substantial adduct-specific nuclear staining was foun
d in basal epithelial and glandular cells of the hamster; in the same
cells of rat and mouse only a weak nuclear staining was found. In the
lung, a common target for NNK-induced tumourigenesis, the formation of
O-6-meGua and 7-meGua was restricted predominantly to bronchial and p
roximal bronchiolar epithelium. Nuclear staining in the rat was occasi
onally found in alveolar cells and was also observed in hepatocytes. I
n the three species investigated, O-6-meGua- and 7-MeGua-specific nucl
ear staining was found in target and non-target tissues. Apparently, a
nd in analogy with results obtained in other studies, the species-spec
ific organotropy for tumour formation of M?TK is not exclusively deter
mined by DNA methylation. Expanding methylation data with literature d
ata on factors considered to be involved in tumour formation, namely p
roliferation, toxicity and DNA repair among others, still did not lead
to a satisfactory explanation for the species-specific organotropy ob
served. Additional factors (yet to be identified), need to be taken in
to account in order to explain (and predict) tumourigenic effects indu
ced by monofunctional methylating agents.