Extrahepatic Cancer Suppresses Nuclear Receptor–Regulated Drug Metabolism

Abstract

To determine the mechanisms by which tumors situated in extrahepatic sites can cause profound changes in hepatic drug clearance, contributing to altered drug response and chemotherapy resistance. We studied in wild-type or transgenic CYP3A4 reporter mice implanted with the murine Engelbreth-Holm-Swarm sarcoma changes in nuclear receptor and hepatic transcription factor expression and/or function, particularly related to CYP3A gene regulation. Repression of hepatic CYP3A induction was dramatic and associated with reduced levels of C/EBPβ isoforms, impaired pregnane X receptor, and constitutive androstane receptor function. Unexpectedly, extrahepatic tumors strongly reduced nuclear accumulation of retinoid X receptor alpha (RXRα) in hepatocytes, providing a potential explanation for impaired function of nuclear receptors that rely on RXRα dimerization. Profiling revealed 38 nuclear receptors were expressed in liver with 14 showing between 1.5- and four-fold reduction in expression in livers of tumor-bearing animals, including Car, Trβ, Lxrβ, Pparα, Errα/β, Reverbα/β, and Shp. Altered Pparα and γ induction of target genes provided additional evidence of perturbed hepatic metabolic control elicited by extrahepatic tumors. Extrahepatic malignancy can affect hepatic drug metabolism by nuclear receptor relocalization and decreased receptor expression and function. These findings could aid the design of intervention strategies to normalize drug clearance and metabolic pathways in cancer patients at risk of chemotherapy-induced toxicity or cancer cachexia.