Normal Bronchial Epithelial Cell Expression of Glutathione Transferase P1, Glutathione Transferase M3, and Glutathione Peroxidase Is Low in Subjects with Bronchogenic Carcinoma
2000
Normal bronchial epithelial cells (NBECs) are at risk for damage
from inhaled and endogenous oxidative species and from epoxide
metabolites of inhaled polycyclic aromatic hydrocarbons.
Epidemiological and in vitro data suggest that
interindividual variation in this risk may result from variation in
NBEC expression of enzymes that inactivate reactive species by
conjugating them to glutathione. Quantitative competitive reverse
transcription-PCR was used to measure mRNA levels of glutathione
transferases (GSTs) and glutathione peroxidases (GSHPxs) in primary
NBECs from subjects with or without bronchogenic carcinoma. Mean
expression levels (mRNA/10 3 β-actin mRNA) in NBECs
from 23 subjects without bronchogenic carcinoma compared to those from
11 subjects with bronchogenic carcinoma respectively (in parentheses)
were: mGST (26.0, 6.11), GSTM3 (0.29, 0.09), combined GSTM1,2,4,5
(0.98, 0.60), GSTT1 (0.84, 0.76), GSTP1 (287, 110), GSHPx (140, 62.1),
and GSHPxA (0.43, 0.34). Levels of GSTP1, GSTM3, and GSHPx were
significantly ( P < 0.05) lower in NBECs
from subjects with bronchogenic carcinoma. Further, the gene
expression index formed by multiplying the values for mGST × GSTM3 × GSHPx × GSHPxA × GSTP1 had a sensitivity (90%) and specificity
(76%) for detecting NBECs from bronchogenic carcinoma subjects that
was better than any individual gene. In cultured NBECs derived from
eight individuals without bronchogenic carcinoma and incubated under
identical conditions such that environmental effects were minimized,
the mean level of expression and degree of interindividual variation
for each gene evaluated was less than that observed in primary NBECs.
Data from these studies support the hypotheses that ( a )
interindividual variation in risk for bronchogenic carcinoma results in
part from interindividual variation in NBEC expression of antioxidant
genes; ( b ) gene expression indices will better identify
individuals at risk for bronchogenic carcinoma than individual gene
expression values; and ( c ) both hereditary and
environmental exposures contribute to the level of and interindividual
variation in gene expression observed in primary NBECs. Many
epidemiological studies have been designed to evaluate risk associated
with polymorphisms or gene expression levels of putative susceptibility
genes based on measurements in surrogate tissues, such as peripheral
blood lymphocytes. Based on data presented here, it will be important
to include the assessment of NBECs in future studies. Measurement of
antioxidant gene expression in NBECs may identify the 5–10% of
individuals at risk for bronchogenic carcinoma. Bronchoscopic sampling
of NBECs from smokers and ex-smokers then will allow susceptible
individuals to be entered into surveillance and/or chemoprevention
studies.
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