Carcinogenesis, Vol 18, 1889-1895, Copyright © 1997 by Oxford University Press
Y Liu, S Egyhazi, J Hansson, SV Bhide, PS Kulkarni and RC Grafstrom
Extracts prepared from tissue specimens of normal, non-tumourous human
buccal mucosa, and cultured buccal epithelial cells and fibroblasts,
exhibited O6-methylguanine-DNA methyltransferase (MGMT) activity by
catalysing the repair of the premutagenic O6-methylguanine lesion in
isolated DNA with rates of 0.2 to 0.3 pmol/mg protein. An SV40 T
antigen-immortalized buccal epithelial cell line termed SVpgC2a and a
buccal squamous carcinoma line termed SqCC/Y1, both of which lack normal
tumour suppressor gene p53 function, exhibited about 50 and 10% of the MGMT
activity of normal cells, respectively. The normal, experimentally
transformed and tumourous buccal cell types showed MGMT mRNA levels which
correlated with their respective levels of MGMT activity. Exposure of
buccal cell cultures to various organic or water- based extracts of
products related to the use of tobacco and betel quid, decreased both cell
survival (measured by reduction of tetrazolium dye) and MGMT activity
(measured subsequently to the exposures in cellular extracts). Organic
extracts of bidi smoke condensate and betel leaf showed higher potency than
those of tobacco and snuff. An aqueous snuff extract also decreased both
parameters, whereas an aqueous areca nut extract was without effect. The
well- established sulph-hydryl-reactive agent Hg2+, a corrosion product of
dental amalgam, served as a positive control and decreased MGMT activity
following treatment of cells within a range of 1-10 microM. Taken together,
significant MGMT activities were demonstrated in buccal tissue specimens
and in the major buccal mucosal cell types in vitro. Lower than normal MGMT
activity in two transformed buccal epithelial cell lines correlated with
decreased MGMT mRNA and lack of functional p53. Finally, in vitro
experiments suggested the potential inhibition of buccal mucosal MGMT
activity by complex mixtures present in the saliva of tobacco and betel nut
chewers.
ARTICLES
O6-methylguanine-DNA methyltransferase activity in human buccal mucosal tissue and cell cultures. Complex mixtures related to habitual use of tobacco and betel quid inhibit the activity in vitro
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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