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Hepatic Drug-metabolizing Enzymes in Primary and Secondary Tumors of Human Liver¹

Department of Pharmacology and Experimental Therapeutics [M. E. M., F. C. K.] and Surgical Oncology Division [M. S. D., E. G. E.], University of Maryland School of Medicine, Baltimore, Maryland 21201; and Department of Biochemistry and Center in Molecular Toxicology [F. P. G.], Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Significant increases in activities of epoxide hydrolase, UDP-glucuronosyltransferase, and glutathione S-transferase, and marked reductions in cytochrome P-450 mixed-function oxidase systems occur in hyperplastic nodules induced in rat liver by chemical mutagens. In contrast, activities of both oxidative (Phase I) and conjugative (Phase II) enzymes are decreased in hepatocellular carcinomas induced by peroxisome proliferators. The present work compares alterations induced by chemical mutagens or peroxisome proliferators with changes in enzyme activities that occur in primary and secondary hepatic tumors in man. The above activities, along with ß-glucuronidase and arylsulfatase, were measured in liver samples from 6 normal livers obtained at immediate autopsy, and liver specimens obtained by surgical biopsy from the following patients: 8 with hepatomas, 5 with nonmetastatic colorectal carcinomas, and 14 with metastatic colorectal carcinomas. Cytochromes P-450_MP and P-450_NF in addition to epoxide hydrolase were measured by immunoquantitation. Enzymes involved in conjugation reactions were either assayed fluorometrically (UDP-glucuronosyltransferase, ß-glucuronidase, sulfotransferase, and sulfatase) or spectrophotometrically (glutathione S-transferase) using umbelliferyl substrates or 1-chloro-2,4-dinitrobenzene. Secondary hepatic tumors showed no significant change in drug-metabolizing enzymes, in contrast to primary hepatomas, which displayed decreases in all of the measured drug metabolizing enzymes. Arylsulfatase was markedly depressed in primary hepatomas (14% of normal values). Thus, activities of drug-metabolizing enzymes in human primary tumors resemble those associated with altered hepatic foci induced by peroxisome proliferators such as ciprofibrate. The marked decreases in sulfatase that occurred in primary but not in secondary human tumors suggest that sulfation of endogenous compounds and xenobiotics may differ in patients with primary and secondary hepatic tumors.

¹ Supported, in part, by NIH Grants CA-20807 and CA-30907, and American Cancer Society Institutional Research Grant IN-147D, Maryland Cancer Program, University of Maryland.

² Current address: Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt.

³ To whom requests for reprints should be addressed, at Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore St., Baltimore, MD 21201.

Received 7/ 2/86. Revised 10/ 8/86. Accepted 10/10/86.

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