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Transcriptional Repression of Hepatic Cytochrome P450 3A4 Gene in the Presence of Cancer

Authors' Affiliations: Departments of ¹ Pharmacology and ² Clinical Pharmacology, University of Sydney, Sydney, New South Wales, Australia; ³ Molecular Pharmacology Laboratory and ⁴ Transgenic Animal Facility, Westmead Millennium Institute, Westmead, New South Wales, Australia; ⁵ Johnson and Johnson Research Australia, Eveleigh, New South Wales, Australia; and ⁶ University of Sydney, Sydney Cancer Centre and ⁷ Cancer Pharmacology Unit, ANZAC Research Institute, Concord RG Hospital, Concord, New South Wales, Australia

Requests for reprints: Graham R. Robertson, Cancer Pharmacology Unit, ANZAC Research Institute, Concord Repatriation General Hospital, Concord, New South Wales 2139, Australia. Phone: 61-2-9767-5753; Fax: 61-2-9767-8069; E-mail: grobertson{at}med.usyd.edu.au.

Purpose: Many chemotherapeutic drugs have an inherent lack of safety due to interindividual variability of hepatic cytochrome P450 (CYP) 3A4 drug metabolism. This reduction in CYP3A4 in cancer patients is possibly mediated by cytokines associated with tumor-derived inflammation. We sought to examine this link by using an explant sarcoma in a novel transgenic mouse model of human CYP3A4 regulation.

Experimental Design: Engelbreth-Holm-Swarm sarcoma cells were injected into the hindlimb of transgenic CYP3A4/lacZ mice. Hepatic expression of the human CYP3A4 transgene was analyzed by direct measurement of the reporter gene product, ß-galactosidase enzyme activity. Hepatic expression of murine Cyp3a was analyzed at the mRNA, protein, and function levels. The acute phase response was assessed by examining cytokines [interleukin-6 (IL-6) and tumor necrosis factor] in serum, liver, or tumor as well as hepatic expression of serum amyloid protein P.

Results: Engelbreth-Holm-Swarm sarcoma elicited an acute phase response that coincided with down-regulation of the human CYP3A4 transgene in the liver as well as the mouse orthologue Cyp3a11. The reduction of murine hepatic Cyp3a gene expression in tumor-bearing mice resulted in decreased Cyp3a protein expression and consequently a significant reduction in Cyp3a-mediated metabolism of midazolam. Circulating IL-6 was elevated and IL-6 protein was only detected in tumor tissue but not in hepatic tissue.

Conclusions: The current study provides a mechanistic link between cancer-associated inflammation and impaired drug metabolism in vivo. Targeted therapy to reduce inflammation may provide improved clinical benefit for chemotherapy drugs metabolized by hepatic CYP3A4 by improving their pharmacokinetic profile.

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