[Screening of principal enzymes involved in the metabolism of anticancer drugs in human and murine colonic tumors].
Since drug-metabolizing enzymes may influence the toxic response of tissues or organs to drugs, we studied their expression in human and colon tumor tissues, in an attempt to find new targets for chemotherapy and also to explain the intrinsic drug-insensitivity of most colon tumors to anticancer drugs. In the present work, we compared human colorectal tumors and peritumoral tissues to a mouse colorectal tumor (Co38) and normal murine colon with regard to their main drug-metabolizing enzyme systems. We investigated cytochromes P-450 (1A1/1A2, 2B1/B2, 2C, 2E1, 3A) and epoxide hydrolase (EH) by immunoblotting. Total glutathione (GSH) and the activities of the following enzymes: total GST, selenium-independent glutathione peroxidase (GPX), 1,2-dichloro-4-nitrobenzene-GST (DCNB-GST), ethacrynic acid-GST (EA-GST), UDP-glucuronosyltransferase 1 (UDPGT), beta-glucuronidase (beta G), sulfotransferase (ST) and sulfatase (S) were investigated by fluorometric and spectrophotometric assays. Results obtained by immunoblotting showed that mouse colon tumor Co38 did not express any of the probed cytochromes P-450, whereas human tumors showed the presence of cytochrome P-450 3A. EH was not expressed in either mouse colon tumor Co38 or normal mouse colon, whereas it was expressed in human peritumoral and tumoral colon tissues at similar levels. GPX and EA-GST were detected in all tumoral and non tumoral tissues of both species. DCNB-GST was expressed in all murine tissues investigated, but was not found in human tissues. For human peritumoral and tumoral colorectal tissues there was no significant difference between GST isoenzymes levels, whereas mouse colon tumor Co38 had a lower expression of DCNB-GST and EA-GST compared to normal mouse colon. No significant difference was observed between human tumors and peritumoral tissues for total GST, UDPGT1, beta G, ST and S activities. For murine colon tissues, the conjugation pathways (total GST, UDPGT1 and ST) were lower in Co38, whereas the opposite was observed for the hydrolytic enzymes (beta G and S). In conclusion, despite similarities between human and murine colon tumors, mouse colon tumor Co38 appears different from human colon tumors for many drug-metabolizing enzyme systems. These interspecies differences may have implications with regard to drug screening methodologies and preclinical evaluation of candidate anticancer drugs useful in the chemotherapy of human colorectal tumors.
Massaad
L
L
Laboratoire de pharmacologie clinique, Institut Gustave-Roussy (INSERM U-140, CNRS URA-147), Villejuif, France.
de Waziers
I
I
Ribrag
V
V
Janot
F
F
Morizet
J
J
Beaune
P H
PH
Gouyette
A
A
Chabot
G G
GG
D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism*; D013429:Sulfatases / Q000378:metabolism
D000970:Antineoplastic Agents; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D013429:Sulfatases; D005966:Glucuronidase; D004851:Epoxide Hydrolases
Dépistage des principaux enzymes impliqués dans le métabolisme des médicaments anticancéreux dans les tumeurs coliques humaines et murines.