Expression of xenobiotic-metabolizing enzymes by primary and secondary hepatic tumors in man

Abstract

Purpose : To determine the immunohistochemical expression of xenobiotic-metabolising enzymes (XME) in normal livers, primary hepatocellular carcinomas (hepatomas) and secondary hepatic tumors from colonic primary tumors. Methods and Materials : The expression of XME in primary ( n = 16) and secondary ( n = 21) hepatic tumors and patients with no malignancies ( n = 20) were investigated using polyclonal antibodies raised against the following rat enzymes CYP1A1 CYP2B1, CYP2C6, CYP3Al, CYP4A1, cytochrome P-450 reductase, epoxide hydrolase and testosterone UDP-glucuronyl transferase. The rat cytochrome P-450 antibodies recognize various human isoenzymes within the same gene family. Immunohistochemistry was undertaken using the immunoperoxidase and alkaline phosphatase anti-alkaline phosphatase techniques. Results : There was a reduction in the overall expression of all XME by tumor tissue compared to adjacent non-neoplastic liver cells ( p = 0.008), more in livers with secondary tumors ( p < 0.0001) and reduced expression of XME by hepatomas and secondary liver tumors compared to livers with no malignancy. A tendency for higher expression of all XME by nonneoplastic liver cells from patients with hepatomas relative to nonmalignant livers was observed, with significantly higher expression of CYP3A4/5 and testosterone UDP-GT enzymes (odds ratio 3.12; CI 1.59-6.10). Conclusion : The expression of XME by tumor tissue is reduced in primary and secondary hepatic malignancies. The expression of XME by nonneoplastic liver cells is higher in patients with hepatomas than patients with no hepatic malignancies. These alterations in XME activities may have important therapeutic implications in the response and toxicity to systemic anti-cancer therapy, due to altered pharmacokinetics. In addition, differential expression of these enzymes by normal and malignant cells may be important for the rational design of selective anti-tumor drugs.