Tumors and Peritumoral Tissues Main Drug-metabolizing Enzyme Systems in Human Breast

In an attempt to better understand breast tumors sensitivity or resis tance to anticancer drugs, the main drug-metabolizing enzyme systems were evaluated in both breast tumors and their corresponding peritumoral tissues in 12 patients. The following enzymes were assayed by Western blot: cytochromes P-4SO (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); glutathione .S'-transferases (GST-a, -u, and -TI); and epoxide hydrolase. The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays: GST; total glutathione; I 1)1'glucuronosyltransferase; ß-glucuronidase; sulfotransferase; and sulfa tase. Results showed the absence of all probed cytochromes P-450 in both tumoral and peritumoral tissues. GST activity was significantly (P < 0.05) higher in tumors (mean ±SD, 399 ±362 nmol/min/mg) than in corre sponding peritumoral tissues (86 ±67). The GST isoenzymes GST-u and GST-IT (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3and 5-fold, respectively). Both GST-u and GST-m levels were significantly correlated with GST activity. GST-a was not detected in either tumoral or peritumoral tissues. Glu tathione levels in tumors (22 ±23 nmol/mg protein) were not statistically different from peritumoral tissues (11 ±12). Epoxide hydrolase was ex pressed at similar levels in tumors and peritumoral tissues. The glucuronide-forming enzyme UDP-glucuronosyltransferase was 5-fold lower in tumors (0.1 ±0.2 nmol/h/mg) than in peritumoral tissues (0.5 ±I), whereas the opposite was observed for the hydrolytic enzyme ß-glucuronidase, which was 6-fold higher in tumors (736 ±1392 nmol/h/mg) compared to peritumoral tissues (125 ±75). No difference was noted between tumoral and peritumoral tissues for sulfotransferase ( I ±2 nmol/h/mg), but the corresponding hydrolytic enzyme (sulfatase) was 2-fold higher in tumoral tissues (14 ±15 nmol/h/mg) than in peritumoral tissues (6 ±2). In con clusion, several differences were observed between human breast tumors and peritumoral tissues for many conjugating enzymes (GST-u, GST-m, and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and ß-glucuronidase). These noteworthy differences between tumoral and per itumoral tissues with regard to their main drug-metabolizing enzymes could play a role in the relative drug sensitivity or insensitivity of human breast cancer tissues to chemotherapeutic agents and could be potential targets for chemotherapeutic interventions.