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Main drug- and carcinogen-metabolizing enzyme systems in human non-small cell lung cancer and peritumoral tissues
C Toussaint1, N Albin, L Massaad
1Département de Pharmacotoxicologie et Pharmacogénétique, Institut Gustave-Roussy (INSERM U 140 and CNRS URA 147), Villejuif, France.
Abstract:
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.
Insights
Drug-metabolizing enzymes like cytochrome P-450 1A1/1A2 and epoxide hydrolase differ between non-small cell lung tumors and normal tissues. These variations may influence anticancer drug sensitivity in lung cancer patients.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- Drug-metabolizing enzymes (DMEs) are crucial for xenobiotic metabolism and can influence cancer development and drug response.
- Non-small cell lung cancer (NSCLC) is a major cause of cancer-related mortality, and understanding its molecular underpinnings is vital for effective treatment.
Purpose of the Study:
- To investigate the expression and activity of key drug-metabolizing enzyme systems in human NSCLC tumors versus adjacent non-tumoral lung tissues.
- To elucidate the potential role of these DMEs in NSCLC carcinogenesis and sensitivity to anticancer therapies.
Main Methods:
- Western blot analysis was used to quantify cytochromes P-450 (CYPs) and epoxide hydrolase.
- Spectrophotometric and fluorometric assays measured the activity of glutathione S-transferase (GST), UDP-glucuronosyltransferase, and sulfotransferase pathways.
- Enzyme levels and activities were compared between tumoral and non-tumoral lung tissues from 12 NSCLC patients.
Main Results:
- Cytochrome P-450 1A1/1A2 (CYP1A1/1A2) levels were significantly lower (3-fold) in NSCLC tumors compared to non-tumoral tissues (P < 0.05).
- Epoxide hydrolase activity was also significantly decreased in tumoral tissues (P < 0.05).
- No significant differences were observed in the glutathione, glucuronide, or sulfate metabolic pathways between tumor and non-tumor tissues.
Conclusions:
- NSCLC tumors exhibit distinct profiles of drug-metabolizing enzymes, specifically reduced levels of CYP1A1/1A2 and epoxide hydrolase, compared to adjacent normal lung tissue.
- These enzymatic differences may be linked to malignant transformation and could impact the efficacy and toxicity of anticancer drugs.
- Further research is warranted to explore the clinical implications of these DME alterations in NSCLC treatment strategies.