Normal bronchial epithelial cell expression of glutathione transferase P1,glutathione transferase M3, and glutathione peroxidase is low in subjects with bronchogenic carcinoma

Normal bronchial epithelial cells (NBECs) are at risk for damage from inhal ed and endogenous oxidative species and from epoxide metabolites of inhaled polycyclic aromatic hydrocarbons. Epidemiological and in vitro data sugges t 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 glutath ione peroxidases (GSHPxs) in primary NBECs from subjects with or without br onchogenic carcinoma. Mean expression levels (mRNA/10(3) beta-actin mRNA) i n NBECs from 23 subjects without bronchogenic carcinoma compared to those f rom 11 subjects with bronchogenic carcinoma respectively tin parentheses) w ere: mGST (26.0, 6.11), GSTM3 (0.29, 0.09), combined GSTM1,2,4,5 (0.98, 0.6 0), 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) lon er in NBECs from subjects with bronchogenic carcinoma. Further, the gen e expression index formed by multiplying the values for mGST x GSTM3 x GSHP x x GSHPxA x GSTP1 had a sensitivity (90%) and specificity (76%) for detect ing NBECs from bronchogenic carcinoma subjects that was better than any ind ividual gene. Zn cultured NBECs derived from eight individuals without bron chogenic carcinoma and incubated under identical conditions such that envir onmental effects were minimized, the mean level of expression and degree of interindividual variation for each gene evaluated was less than that obser ved 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 inte rindividual variation in gene expression observed in primary NBECs. Many ep idemiological studies have been designed to evaluate risk associated with p olymorphisms or gene expression levels of putative susceptibility genes bas ed on measurements in surrogate tissues, such as peripheral blood lymphocyt es. Based on data presented here, it will be important to include the asses sment of NBECs in future studies. Measurement of antioxidant gene expressio n in NBECs may identify the 5-10% of individuals at risk for bronchogenic c arcinoma. Bronchoscopic sampling of NBECs from smokers and ex-smokers then will allow susceptible individuals to be entered into surveillance and/or c hemoprevention studies.