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

In an attempt to better understand breast tumors sensitivity or resistance 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-450 (1A1/A2, 2B1/B2, 2C8-10, 2E1, 3A4); glutathione S -transferases (GST-α, -µ, and -π); and epoxide hydrolase. The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays; GST; total glutathione; UDP-glucuronosyltransferases; β-glucuronidase; sulfotransferase; and sulfatase. 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 corresponding peritumoral tissues (86 ± 67). The GST isoenzymes GST-µ and GST-π (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3- and 5-fold, respectively). Both GST-µ and GST-π levels were significantly correlated with GST activity. GST-α was not detected in either tumoral or peritumoral tissues. Glutathione levels in tumors (22 ± 23 nmol/mg protein) were not statistically different from peritumoral tissues (11 ± 12). Epoxide hydrolase was expressed 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 ± 1), whereas the opposite was observed for the hydrolytic enzyme β-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 (1 ± 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 conclusion, several differences were observed between human breast tumors and peritumoral tissues for many conjugating enzymes (GST-µ, GST-π, and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and β-glucuronidase). These noteworthy differences between tumoral and peritumoral 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.