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Main Drug-metabolizing Enzyme Systems in Human Breast Tumors and Peritumoral Tissues¹

Département de Pharmaco-toxicologie et Pharmacogénétique [INSERM U 140 and CNRS URA 147) [N. A., L. M., C. T., J. M., O. P., A. G., G. G. C.], and Département d'Anatomo-Pathologie [M-C. M.], Institut Gustave-Roussy, 94805 Villejuif Cedex, France

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-, -µ, and -); and epoxide hydrolase. The activity of the following enzymes or cofactor were determined by spectrophotometric or fluorometric assays; GST; total glutathione; UDP-glucuronosyltransferases; ß-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- (determined by immunoblotting) were also higher in tumors than in corresponding peritumoral tissues (3- and 5-fold, respectively). Both GST-µ and GST- levels were significantly correlated with GST activity. GST- 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 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 (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-, and UDP-glucuronosyltransferase) and hydrolytic enzymes (sulfatase and ß-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.

¹ This work was supported by the Fondation pour la Recherche Médicale, the Institut National de la Santé et de la Recherche Médicale (INSERM), and the Centre National de la Recherche Scientifique (CNRS).

² To whom requests for reprints should be addressed, at Institut Gustave-Roussy, Département de Pharmaco-toxicologie et Pharmacogénétique, Pavillon de Recherche 2, 94805 Villejuif Cedex, France.

Received 2/ 4/93. Accepted 5/24/93.

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