Main drug- and carcinogen-metabolizing enzyme systems in human non-small cell lung cancer and peritumoral tissues.
To better understand the importance of drug-metabolizing enzymes in carcinogenesis and anticancer drug sensitivity of human non-small cell lung cancer, we studied the main drug-metabolizing enzyme systems in both lung tumors and their corresponding nontumoral lung tissues in 12 patients. The following enzymes were assayed by Western blot analysis: cytochromes P-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); epoxide hydrolase; and glutathione S-transferase isoenzymes (GST-alpha, -mu, and -pi). The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: glutathione S-transferase (GST); total glutathione; UDP-glucuronosyltransferase; beta-glucuronidase; sulfotransferase; and sulfatase. Results showed the presence of cytochrome P-450 1A1/1A2 in both tumoral and nontumoral tissues. P-450 1A1/1A2 levels were 3-fold lower in tumors compared to corresponding nontumoral tissues (P < 0.05). None of the other probed cytochromes P-450 were detected in either tumoral or nontumoral lung tissues. For the glutathione system, no significant difference between tumoral and nontumoral tissues was observed (GST activity, glutathione content, GST-alpha, -mu, and -pi). A positive linear correlation was observed between GST activity and GST-alpha or GST-pi. No significant difference was observed for the glucuronide and the sulfate pathways and their corresponding hydrolytic enzymes. Epoxide hydrolase was significantly decreased in tumors compared to nontumoral lung tissues (P < 0.05). In conclusion, these results showed differences between non-small cell lung tumors and nontumoral tissues for cytochrome P-450 1A1/1A2 and epoxide hydrolase. These differences between tumors and peritumoral tissues with regard to these drug-metabolizing enzymes could reflect differences occurring after malignant transformation and may play a role in drug sensitivity to anticancer drugs.
Toussaint
C
C
Département de Pharmacotoxicologie et Pharmacogénétique, Institut Gustave-Roussy (INSERM U 140 and CNRS URA 147), Villejuif, France.
Albin
N
N
Massaad
L
L
Grunenwald
D
D
Parise
O
O
Morizet
J
J
Gouyette
A
A
Chabot
G G
GG
D000328:Adult; D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000302:isolation & purification / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000201:enzymology*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism; D012907:Smoking; D013429:Sulfatases / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism
D002273:Carcinogens; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D015238:Sulfotransferases; D013429:Sulfatases; D005966:Glucuronidase; D004851:Epoxide Hydrolases; D005978:Glutathione