MAIN DRUG-METABOLIZING ENZYME-SYSTEMS IN HUMAN NON-HODGKINS-LYMPHOMASSENSITIVE OR RESISTANT TO CHEMOTHERAPY

Non-Hodgkin's lymphomas (NHL) are one of the most chemosensitive human malignancies. Complete response (CR) is often achieved, but many pati ents relapse and a second CR is difficult to obtain because of the dev elopment of chemoresistance. In an attempt to better understand the bi ology and the chemosensitivity of these lymphoid tumors, we assessed t he main drug-metabolizing enzyme systems in normal lymphocytes, chemos ensitive NHL and chemoresistant NHL. Cytochromes P-450(1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4), epoxide hydrolase and glutathione S-transferases ( GST-alpha, -mu, -pi) were assayed by immunoblotting. UDP-glucuronosylt ransferase, beta-glucuronidase, sulfotransferase, sulfatase, GST activ ity, and glutathione (GSH) content, were determined by spectral assays , Results showed the absence of all probed cytochromes P-450 in normal lymphocytes and NHL cells tested. GST activity was significantly lowe r in chemoresistant NHL compared to normal lymphocytes. GST-alpha was not detected in either normal lymphocytes or NHL cells. GST-pi was the predominant isoenzyme, and GST-mu was not detected in chemosensitive NHL. GSH content was significantly lower in chemoresistant NHL compare d to other lymphoid tissues tested. The conjugating enzymes UDP-glucur onosyltransferase and sulfatase were similar in either chemoresistant NHL compared to chemosensitive NHL. The activity of the hydrolytic enz yme beta-glucuronidase was lower in chemoresistant compared to chemose nsitive NHL, whereas sulfatase was higher in sensitive NHL compared to normal lymphocytes. Epoxide hydrolase was not detected in either norm al or NHL cells tested. In conclusion, these studies did not show any cytochrome P-450 in human lymphoid cells tested, but pointed out notew orthy differences for other enzyme systems tested. These data are of i mportance to further understand the mechanisms of drug resistance in h uman NHL.