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Comparison of Mouse and Human Colon Tumors with Regard to Phase I and Phase II Drug-metabolizing Enzyme Systems¹

Laboratoire de Pharmacologie Clinique, Institut Gustave-Roussy, (INSERM U 140 and CNRS URA 147), 94805 Villejuif Cedex [L. M., V. R., F. J., J. M., A. G., G. G. C.], and Laboratoire INSERM U 75, Centre Hospitalier Universitaire Necker Enfants Malades, 75730 Paris Cedex 15 [I. de W., P. H. B.], France.

² To whom requests for reprints should be addressed, at Institut Gustave-Roussy, Laboratoire de pharmacologie clinique, Pavillon de recherche 2, 94805 Villejuif Cedex, France.

Since human colorectal tumors are insensitive to most chemotherapeutic agents, there is a need for the discovery of new drugs that would show activity against this disease. In an attempt to better appreciate the relevance of a widely used mouse colon tumor (colon adenocarcinoma Co38) as a screening model for human colorectal tumors, we compared the main phase I and phase II drug-metabolizing enzyme systems in both tumoral and nontumoral colon tissues. The following enzymes were assayed by Western blot: cytochromes P-450 (1A1/A2, 2B1/B2, 2C, 2E1, and 3A), epoxide hydrolase, and glutathione-S-transferases (GST-, -µ, and -). The activities of the following enzymes or cofactors were determined by spectrophotometric or fluorometric assays: total cytochrome P-450, 1-chloro-2,4-dinitrobenzene-GST, selenium-independent glutathione peroxidase, 3,4-dichloronitrobenzene-GST, ethacrynic acid-GST, total glutathione, epoxide hydrolase, UDP-glucuronosyltransferase, β-glucuronidase, sulfotransferase, and sulfatase. Results obtained by Western blot showed that mouse colon adenocarcinoma Co38 did not express any of the probed cytochromes P-450, whereas human colorectal tumors expressed only low levels of cytochrome P-450 3A. GST- and GST- were detected in all tumoral and nontumoral tissues of both species. The neutral GST-µ was expressed in all murine tissues investigated and was found to be polymorphic in human tissues. For human peritumoral and tumoral colorectal tissues there was no significant difference between GST isoenzyme levels, whereas mouse colon adenocarcinoma Co38 had a lower expression of GST-µ and GST-, compared to normal mouse colon. Enzymatic activities for glutathione peroxidase, 3,4-dichloronitrobenzene-GST, and ethacrynic acid-GST confirmed the Western blot results for GST-, GST-µ, and GST-, respectively. Total GSH levels were similar between murine and human tumors but were 3-fold higher in human tumors than in peritumoral tissues, whereas they were 7-fold lower in mouse colon tumor Co38, compared to normal mouse colon. Epoxide hydrolase was not expressed in either mouse colon adenocarcinoma Co38 or normal mouse colon tissues, whereas it was expressed in human colon peritumoral and tumoral tissues at similar levels. No significant difference was observed between human tumors and peritumoral tissues for UDP-glucuronosyltransferase, β-glucuronidase, sulfotransferase, and sulfatase. For murine colon tissues, the conjugation pathways (UDP-glucuronosyltransferase and sulfotransferase) were lower in colon adenocarcinoma Co38, whereas the converse was observed for the corresponding hydrolytic enzymes β-glucuronidase and sulfatase). In conclusion, similarities were noted between mouse colon adenocarcinoma Co38 and human colon tumors with regard to the absence of most forms of cytochromes P-450 except cytochrome P-450 3A, which was detected in human tumors only. However, for most phase II drug-metabolizing pathways the mouse model was qualitatively and quantitatively different from human colon tissues. These noteworthy interspecies differences may have implications with regard to drug-screening methodologies and preclinical evaluation of candidate anticancer drugs for the chemotherapy of human colorectal tumors.

¹ This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), the Fondation pour la Recherche Médicale, and the Association pour la Recherche sur le Cancer (Grants 6604 and 6917).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 4/ 8/92. Accepted 9/22/92.

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